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Publisher: Elsevier   (Total: 3160 journals)

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Showing 1201 - 1400 of 3160 Journals sorted alphabetically
Growth Factors and Cytokines in Health and Disease     Full-text available via subscription   (Followers: 1)
Growth Hormone & IGF Research     Hybrid Journal   (Followers: 17, SJR: 1.059, CiteScore: 2)
Gynecologic Oncology     Hybrid Journal   (Followers: 25, SJR: 2.339, CiteScore: 4)
Gynecologic Oncology Reports     Open Access   (Followers: 10, SJR: 0.307, CiteScore: 1)
Gynécologie Obstétrique & Fertilité     Full-text available via subscription   (Followers: 1)
Habitat Intl.     Hybrid Journal   (Followers: 6, SJR: 1.336, CiteScore: 3)
Hand Clinics     Full-text available via subscription   (Followers: 5, SJR: 0.556, CiteScore: 1)
Hand Surgery and Rehabilitation     Full-text available via subscription   (Followers: 4, SJR: 0.358, CiteScore: 1)
Handai Nanophotonics     Full-text available via subscription  
Handbook of Adhesives and Sealants     Full-text available via subscription   (Followers: 2)
Handbook of Agricultural Economics     Full-text available via subscription   (Followers: 3)
Handbook of Algebra     Full-text available via subscription  
Handbook of Analytical Separations     Full-text available via subscription   (Followers: 3)
Handbook of Behavioral Neuroscience     Full-text available via subscription   (Followers: 3)
Handbook of Biological Physics     Full-text available via subscription  
Handbook of Chemical Neuroanatomy     Full-text available via subscription  
Handbook of Clinical Neurology     Full-text available via subscription   (Followers: 2, SJR: 1.007, CiteScore: 2)
Handbook of Clinical Neurophysiology     Full-text available via subscription  
Handbook of Complex Analysis     Full-text available via subscription  
Handbook of Computational Economics     Full-text available via subscription   (Followers: 2, SJR: 4.16, CiteScore: 2)
Handbook of Defense Economics     Full-text available via subscription   (Followers: 2)
Handbook of Development Economics     Full-text available via subscription   (Followers: 8)
Handbook of Differential Equations: Evolutionary Equations     Full-text available via subscription  
Handbook of Differential Equations: Ordinary Differential Equations     Full-text available via subscription  
Handbook of Differential Equations: Stationary Partial Differential Equations     Full-text available via subscription   (Followers: 2)
Handbook of Differential Geometry     Full-text available via subscription  
Handbook of Dynamical Systems     Full-text available via subscription   (Followers: 1)
Handbook of Econometrics     Full-text available via subscription   (Followers: 10)
Handbook of Economic Forecasting     Full-text available via subscription   (Followers: 3)
Handbook of Economic Growth     Full-text available via subscription   (Followers: 3)
Handbook of Environmental Economics     Full-text available via subscription   (Followers: 3)
Handbook of Experimental Economics Results     Full-text available via subscription   (Followers: 6)
Handbook of Exploration and Environmental Geochemistry     Full-text available via subscription   (Followers: 2)
Handbook of Exploration Geochemistry     Full-text available via subscription   (Followers: 1)
Handbook of Ferromagnetic Materials     Full-text available via subscription   (Followers: 1)
Handbook of Game Theory with Economic Applications     Full-text available via subscription   (Followers: 1)
Handbook of Geophysical Exploration: Seismic Exploration     Full-text available via subscription  
Handbook of Health Economics     Full-text available via subscription   (Followers: 13)
Handbook of Immunohistochemistry and in Situ Hybridization of Human Carcinomas     Full-text available via subscription   (Followers: 1)
Handbook of Income Distribution     Full-text available via subscription   (Followers: 4)
Handbook of Industrial Organization     Full-text available via subscription   (Followers: 5)
Handbook of Intl. Economics     Full-text available via subscription  
Handbook of Labor Economics     Full-text available via subscription   (Followers: 14)
Handbook of Law and Economics     Full-text available via subscription   (Followers: 17)
Handbook of Macroeconomics     Full-text available via subscription   (Followers: 6, SJR: 0, CiteScore: 2)
Handbook of Magnetic Materials     Full-text available via subscription   (Followers: 2, SJR: 0.467, CiteScore: 2)
Handbook of Mathematical Economics     Full-text available via subscription  
Handbook of Mathematical Fluid Dynamics     Full-text available via subscription   (Followers: 2)
Handbook of Metal Physics     Full-text available via subscription  
Handbook of Monetary Economics     Full-text available via subscription   (Followers: 7)
Handbook of Natural Resource and Energy Economics     Full-text available via subscription   (Followers: 5)
Handbook of Numerical Analysis     Full-text available via subscription   (Followers: 5)
Handbook of Perception and Action     Full-text available via subscription   (Followers: 2)
Handbook of Petroleum Exploration and Production     Full-text available via subscription   (Followers: 2)
Handbook of Population and Family Economics     Full-text available via subscription   (Followers: 4)
Handbook of Powder Technology     Full-text available via subscription   (Followers: 6)
Handbook of Public Economics     Full-text available via subscription   (Followers: 1)
Handbook of Regional and Urban Economics     Full-text available via subscription   (Followers: 3)
Handbook of Sensors and Actuators     Full-text available via subscription   (Followers: 10)
Handbook of Social Choice and Welfare     Full-text available via subscription   (Followers: 3)
Handbook of Statistics     Full-text available via subscription   (Followers: 8, SJR: 0.102, CiteScore: 0)
Handbook of Surface Science     Full-text available via subscription   (Followers: 4, SJR: 0.193, CiteScore: 0)
Handbook of Systemic Autoimmune Diseases     Full-text available via subscription   (Followers: 2)
Handbook of the Economics of Art and Culture     Full-text available via subscription   (Followers: 3)
Handbook of the Economics of Education     Full-text available via subscription   (Followers: 9, SJR: 0, CiteScore: 2)
Handbook of the Economics of Finance     Full-text available via subscription   (Followers: 6)
Handbook of the Economics of Giving, Altruism and Reciprocity     Full-text available via subscription   (Followers: 2)
Handbook of the Geometry of Banach Spaces     Full-text available via subscription   (Followers: 1)
Handbook of the History of Logic     Full-text available via subscription   (Followers: 1)
Handbook of Thermal Analysis and Calorimetry     Full-text available via subscription   (Followers: 1)
Handbook of Thermal Conductivity     Full-text available via subscription   (Followers: 4)
Handbook of Vapor Pressure     Full-text available via subscription  
Handbook on the Physics and Chemistry of Rare Earths     Full-text available via subscription   (Followers: 3, SJR: 0.755, CiteScore: 3)
Handbooks of Management Accounting Research     Full-text available via subscription   (Followers: 4)
HardwareX     Open Access  
Harmful Algae     Hybrid Journal   (Followers: 5, SJR: 1.531, CiteScore: 4)
HBRC J.     Open Access   (Followers: 2)
Health & Place     Hybrid Journal   (Followers: 15, SJR: 1.506, CiteScore: 3)
Health Outcomes Research in Medicine     Hybrid Journal   (Followers: 3)
Health Policy     Hybrid Journal   (Followers: 43, SJR: 1.252, CiteScore: 2)
Health Policy and Technology     Hybrid Journal   (Followers: 4, SJR: 0.322, CiteScore: 1)
Health Professions Education     Open Access   (Followers: 3)
Healthcare : The J. of Delivery Science and Innovation     Full-text available via subscription   (Followers: 1)
Hearing Research     Hybrid Journal   (Followers: 11, SJR: 1.35, CiteScore: 3)
Heart & Lung: The J. of Acute and Critical Care     Hybrid Journal   (Followers: 11, SJR: 0.757, CiteScore: 2)
Heart Failure Clinics     Full-text available via subscription   (Followers: 2, SJR: 1.153, CiteScore: 2)
Heart Rhythm     Hybrid Journal   (Followers: 11, SJR: 3.231, CiteScore: 4)
Heart, Lung and Circulation     Full-text available via subscription   (Followers: 9, SJR: 0.599, CiteScore: 1)
HeartRhythm Case Reports     Open Access   (SJR: 0.232, CiteScore: 0)
Heliyon     Open Access   (SJR: 0.355, CiteScore: 1)
Hellenic J. of Cardiology     Open Access   (Followers: 1, SJR: 0.479, CiteScore: 1)
Hematology, Transfusion and Cell Therapy     Open Access   (Followers: 1)
Hematology/Oncology and Stem Cell Therapy     Open Access   (Followers: 4, SJR: 0.532, CiteScore: 1)
Hematology/Oncology Clinics of North America     Full-text available via subscription   (Followers: 6, SJR: 1.282, CiteScore: 3)
Hepatobiliary & Pancreatic Diseases Intl.     Full-text available via subscription   (Followers: 2, SJR: 0.711, CiteScore: 2)
High Energy Density Physics     Hybrid Journal   (Followers: 2, SJR: 0.933, CiteScore: 2)
Hipertensión y Riesgo Vascular     Full-text available via subscription   (SJR: 0.115, CiteScore: 0)
Historia Mathematica     Full-text available via subscription   (Followers: 1, SJR: 0.174, CiteScore: 0)
History of CERN     Full-text available via subscription   (Followers: 1)
History of Neuroscience in Autobiography     Full-text available via subscription   (Followers: 3)
HIV & AIDS Review     Full-text available via subscription   (Followers: 12, SJR: 0.134, CiteScore: 0)
Homeopathy     Hybrid Journal   (Followers: 6, SJR: 0.678, CiteScore: 1)
HOMO - J. of Comparative Human Biology     Hybrid Journal   (Followers: 2, SJR: 0.335, CiteScore: 1)
Hong Kong J. of Nephrology     Open Access   (Followers: 2, SJR: 0.137, CiteScore: 0)
Hong Kong J. of Occupational Therapy     Open Access   (Followers: 43, SJR: 0.237, CiteScore: 1)
Hong Kong Physiotherapy J.     Open Access   (Followers: 14, SJR: 0.183, CiteScore: 0)
Hormigón y Acero     Full-text available via subscription  
Hormones and Behavior     Hybrid Journal   (Followers: 13, SJR: 1.638, CiteScore: 4)
Horticultural Plant J.     Open Access   (Followers: 5)
Hospital Medicine Clinics     Full-text available via subscription   (Followers: 2, SJR: 0.107, CiteScore: 0)
Human Factors in Information Technology     Full-text available via subscription   (Followers: 35)
Human Immunology     Hybrid Journal   (Followers: 18, SJR: 0.856, CiteScore: 2)
Human Movement Science     Hybrid Journal   (Followers: 15, SJR: 0.756, CiteScore: 2)
Human Pathology     Hybrid Journal   (Followers: 26, SJR: 1.304, CiteScore: 3)
Human Pathology : Case Reports     Open Access   (Followers: 2, SJR: 0.136, CiteScore: 0)
Human Resource Management Review     Hybrid Journal   (Followers: 54, SJR: 1.675, CiteScore: 4)
Hydrometallurgy     Hybrid Journal   (Followers: 13, SJR: 1.208, CiteScore: 3)
IATSS Research     Open Access   (SJR: 0.37, CiteScore: 1)
Icarus     Hybrid Journal   (Followers: 74, SJR: 2.037, CiteScore: 3)
ICT Express     Open Access   (SJR: 0.234, CiteScore: 1)
IDCases     Open Access   (SJR: 0.344, CiteScore: 1)
IERI Procedia     Open Access   (Followers: 1)
IFAC-PapersOnLine     Open Access   (SJR: 0.26, CiteScore: 1)
IIMB Management Review     Open Access   (Followers: 9, SJR: 0.24, CiteScore: 1)
IJC Heart & Vessels     Open Access   (Followers: 1)
IJC Heart & Vasculature     Open Access   (Followers: 1, SJR: 0.342, CiteScore: 1)
IJC Metabolic & Endocrine     Open Access   (Followers: 1, SJR: 0.4, CiteScore: 1)
Image and Vision Computing     Hybrid Journal   (Followers: 15, SJR: 0.612, CiteScore: 3)
Imagen Diagnóstica     Full-text available via subscription   (SJR: 0.106, CiteScore: 0)
Imagerie de la Femme     Full-text available via subscription   (Followers: 1, SJR: 0.124, CiteScore: 0)
Immunity     Full-text available via subscription   (Followers: 55, SJR: 13.393, CiteScore: 16)
Immuno-analyse & Biologie Spécialisée     Full-text available via subscription   (Followers: 2)
Immunobiology     Hybrid Journal   (Followers: 9, SJR: 1.1, CiteScore: 3)
Immunology and Allergy Clinics of North America     Full-text available via subscription   (Followers: 6, SJR: 1.132, CiteScore: 3)
Immunology Letters     Hybrid Journal   (Followers: 13, SJR: 1.168, CiteScore: 3)
Immunotoxicology of Drugs and Chemicals: an Experimental and Clinical Approach     Full-text available via subscription   (Followers: 1)
Implantodontie     Full-text available via subscription  
Indagationes Mathematicae     Open Access   (Followers: 1, SJR: 0.685, CiteScore: 1)
Indian Heart J.     Open Access   (Followers: 5, SJR: 0.333, CiteScore: 1)
Indian J. of Medical Specialities     Hybrid Journal   (SJR: 0.118, CiteScore: 0)
Indian J. of Tuberculosis     Full-text available via subscription   (SJR: 0.221, CiteScore: 0)
Indian Pacing and Electrophysiology J.     Open Access   (Followers: 1, SJR: 0.273, CiteScore: 0)
Industrial Chemistry Library     Full-text available via subscription   (Followers: 3)
Industrial Crops and Products     Hybrid Journal   (Followers: 6, SJR: 1.091, CiteScore: 4)
Industrial Marketing Management     Hybrid Journal   (Followers: 23, SJR: 1.663, CiteScore: 4)
Industrial Safety Series     Full-text available via subscription   (Followers: 17)
Infant Behavior and Development     Hybrid Journal   (Followers: 14, SJR: 0.784, CiteScore: 2)
Infectio     Open Access   (SJR: 0.133, CiteScore: 0)
Infection, Disease & Health     Open Access   (Followers: 8, SJR: 0.23, CiteScore: 1)
Infection, Genetics and Evolution     Hybrid Journal   (Followers: 5, SJR: 1.278, CiteScore: 3)
Infectious Disease Clinics of North America     Full-text available via subscription   (Followers: 5, SJR: 2.359, CiteScore: 5)
Informatics in Medicine Unlocked     Open Access   (SJR: 0.224, CiteScore: 1)
Information & Management     Hybrid Journal   (Followers: 56, SJR: 1.628, CiteScore: 5)
Information and Computation     Hybrid Journal   (Followers: 4, SJR: 0.504, CiteScore: 1)
Information and Organization     Hybrid Journal   (Followers: 39, SJR: 1.202, CiteScore: 3)
Information and Software Technology     Hybrid Journal   (Followers: 6, SJR: 0.581, CiteScore: 4)
Information Economics and Policy     Hybrid Journal   (Followers: 5, SJR: 0.63, CiteScore: 1)
Information Fusion     Hybrid Journal   (Followers: 2, SJR: 1.832, CiteScore: 7)
Information Processing & Management     Hybrid Journal   (Followers: 415, SJR: 0.92, CiteScore: 4)
Information Processing in Agriculture     Open Access   (SJR: 0.352, CiteScore: 2)
Information Processing Letters     Hybrid Journal   (Followers: 6, SJR: 0.412, CiteScore: 1)
Information Sciences     Hybrid Journal   (Followers: 475, SJR: 1.635, CiteScore: 5)
Information Security Technical Report     Full-text available via subscription   (Followers: 12)
Information Systems     Hybrid Journal   (Followers: 13, SJR: 0.805, CiteScore: 4)
Infosecurity     Full-text available via subscription   (Followers: 11)
Infrared Physics & Technology     Hybrid Journal   (Followers: 12, SJR: 0.54, CiteScore: 2)
Injury     Hybrid Journal   (Followers: 18, SJR: 0.99, CiteScore: 2)
Injury Extra     Open Access   (Followers: 2)
Inmunología     Full-text available via subscription   (Followers: 2)
Innovative Food Science & Emerging Technologies     Hybrid Journal   (Followers: 5, SJR: 1.201, CiteScore: 3)
Inorganic Chemistry Communications     Hybrid Journal   (Followers: 13, SJR: 0.43, CiteScore: 2)
Inorganica Chimica Acta     Hybrid Journal   (Followers: 9, SJR: 0.485, CiteScore: 2)
Insect Biochemistry and Molecular Biology     Hybrid Journal   (Followers: 3, SJR: 1.912, CiteScore: 4)
Instabilities in Silicon Devices     Full-text available via subscription   (Followers: 1)
Insulin     Full-text available via subscription   (Followers: 6)
Insurance: Mathematics and Economics     Hybrid Journal   (Followers: 9, SJR: 1.083, CiteScore: 2)
Integration, the VLSI J.     Hybrid Journal   (Followers: 6, SJR: 0.223, CiteScore: 1)
Integrative Medicine Research     Open Access   (Followers: 3)
Intellectual Economics     Open Access  
Intelligence     Hybrid Journal   (Followers: 7, SJR: 1.633, CiteScore: 3)
Intensive and Critical Care Nursing     Hybrid Journal   (Followers: 31, SJR: 0.611, CiteScore: 2)
Interdisciplinary Neurosurgery     Open Access   (SJR: 0.164, CiteScore: 0)
Interface Science and Technology     Full-text available via subscription  
Intermetallics     Hybrid Journal   (Followers: 22, SJR: 1.568, CiteScore: 4)
Internet Interventions : The application of information technology in mental and behavioural health     Open Access   (Followers: 4, SJR: 1.962, CiteScore: 4)
Interventional Cardiology Clinics     Full-text available via subscription   (Followers: 3, SJR: 0.156, CiteScore: 0)
Intl. Biodeterioration & Biodegradation     Hybrid Journal   (Followers: 1, SJR: 1.086, CiteScore: 4)
Intl. Business Review     Hybrid Journal   (Followers: 10, SJR: 1.012, CiteScore: 3)
Intl. Communications in Heat and Mass Transfer     Hybrid Journal   (Followers: 21, SJR: 1.553, CiteScore: 5)
Intl. Comparative Jurisprudence     Open Access   (Followers: 2)
Intl. Dairy J.     Hybrid Journal   (Followers: 6, SJR: 1.051, CiteScore: 2)
Intl. Economics     Hybrid Journal   (Followers: 3, SJR: 0.451, CiteScore: 1)
Intl. Emergency Nursing     Hybrid Journal   (Followers: 10, SJR: 0.461, CiteScore: 1)
Intl. Geophysics     Full-text available via subscription   (Followers: 3)
Intl. Immunopharmacology     Hybrid Journal   (Followers: 2, SJR: 1.051, CiteScore: 3)
Intl. J. for Parasitology     Hybrid Journal   (Followers: 11, SJR: 1.638, CiteScore: 4)
Intl. J. for Parasitology : Drugs and Drug Resistance     Open Access   (Followers: 4, SJR: 1.556, CiteScore: 4)
Intl. J. for Parasitology : Parasites and Wildlife     Open Access   (Followers: 2, SJR: 1.455, CiteScore: 3)
Intl. J. of Accounting     Hybrid Journal   (Followers: 1)
Intl. J. of Accounting Information Systems     Hybrid Journal   (Followers: 5, SJR: 0.399, CiteScore: 2)

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Similar Journals
Journal Cover
International Immunopharmacology
Journal Prestige (SJR): 1.051
Citation Impact (citeScore): 3
Number of Followers: 2  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 1567-5769
Published by Elsevier Homepage  [3160 journals]
  • Novel inflammatory cytokines (IL-36, 37, 38) in the aqueous humor from
           patients with chronic primary angle closure glaucoma
    • Abstract: Publication date: June 2019Source: International Immunopharmacology, Volume 71Author(s): Jin-ling Zhang, Xiang-yuan Song, Ya-ying Chen, Thi Hoang Anh Nguyen, Jing-yi Zhang, Shi-san Bao, Yu-yan Zhang Glaucoma eventually leads to optic nerve damage and vision loss without medical intervention. More than 50% of glaucoma caused blindness are attributed to primary angle closure glaucoma, particularly in Asians. It is reported that immune inflammation is involved in the progress of glaucoma.Increased inflammation cytokines are detected in the aqueous humor of chronic primary angle closure glaucoma (CPACG). IL-36, IL-37 and IL-38, are novel cytokines and are involved in many inflammatory diseases, including inflammatory bowel diseases and acute anterior uveitis, but the possible contributing role in the pathogenesis of CPACG is unclear. In our current study, increased IL-36, IL-37 and IL-38 were detected in the aqueous humor of CPACG compared with age-related cataract (ARC). Furthermore, a significant correlation was detected between mean deviation of visual field (MDVF) of CPACG and IL-36, IL-37 or IL-38, respectively. Our data suggest IL-36, IL-37 and IL-38 might contribute to the immunological mediated pathogenesis of CPACG, despite the eye being an immune-privileged organ under normal conditions. The precise underlying mechanism of these cytokines during the development of CPACG remains to be explored. Our findings may be useful in therapeutic targeting of specific pathology.
       
  • Ethyl pyruvate protects against Salmonella intestinal infection in mice
           through down-regulation of pro-inflammatory factors and inhibition of
           TLR4/MAPK pathway
    • Abstract: Publication date: June 2019Source: International Immunopharmacology, Volume 71Author(s): Na Dong, Xinyao Xu, Chenyu Xue, Chensi Wang, Xinran Li, Anshan Shan, Li Xu, Deshan Li Salmonella typhimurium is one of the main causes of intestinal diseases, affecting the health of humans and livestock. Ethyl pyruvate (EP), which is ordinarily an edible spice, has been indicated to exert anti-inflammatory effects and preserve intestinal barrier function. In this study, intestinal immune function and signaling pathways activated by EP were investigated in vivo in S. typhimurium-challenged BALB/c mice and in vitro in RAW264.7 cells. EP improved body weight loss and the organ index of the liver and spleen (p 
       
  • Genistein protects against DSS-induced colitis by inhibiting NLRP3
           inflammasome via TGR5-cAMP signaling
    • Abstract: Publication date: June 2019Source: International Immunopharmacology, Volume 71Author(s): Yu Chen, Thi Ha Le, Qianming Du, Zheng Zhao, Yunxin Liu, Jianjun Zou, Weiwei Hua, Chao Liu, Yubing Zhu NLRP3 inflammasome has been reported to be associated with inflammatory bowel disease including colitis due to its potential ability to induce IL-1β secretion. Emerging studies have demonstrated that Genistein, a major isoflavone, has potential anti-inflammatory effects in murine model colitis. However, its anti-inflammatory mechanism remains unclear. The effects of Genistein in dextran sulfate sodium (DSS)-induced murine colitis via targeting NLRP3 inflammasome was investigated in this study. Also, the mechanisms of protective action of Genistein in DSS-induced colitis may relate to TGR5 signaling. Genistein treatment not only remarkably attenuated loss of body weight and shortening of colon length but also significantly reduced inflammatory cells infiltration and pro-inflammatory mediator production in serum and colon. Moreover, Genistein treatment down-regulated production of caspase-1 and IL-1β and increased intracellular cAMP level, which were similar to the treatment for INT-777, a semi-synthetic TGR5 agonist, in phorbol myristate acetate (PMA)-differentiated monocytic THP-1 cells and U937 cells. These protective effects of Genistein might be attributed by ubiquination of NLRP3 which was induced due to interaction of cAMP with NLRP3. Furthermore, the effects of Genistein on NLRP3 inflammasome disappeared in TGR5-silenced U937 cells. In conclusion, our study unveils that Genistein was able to inhibit NLRP3 inflammasome via TGR5-cAMP signaling in macrophages. It therefore might be a potential effective drug for inflammatory bowel diseases.
       
  • Downregulation of microsomal prostaglandin E synthase-1 (mPGES-1)
           expression in chondrocytes is regulated by MAP kinase phosphatase-1
           (MKP-1)
    • Abstract: Publication date: June 2019Source: International Immunopharmacology, Volume 71Author(s): Lauri Tuure, Mari Hämäläinen, Elina Nummenmaa, Teemu Moilanen, Eeva Moilanen ObjectivesMicrosomal prostaglandin E synthase-1 (mPGES-1) catalyses the formation of PGE2 in inflammatory tissues. It is considered a potential drug target in inflammatory conditions to achieve clinical benefits comparable to NSAIDs with a better tolerability. Inhibitors of mPGES-1 are under development but the pharmacological regulation of mPGES-1 expression remains poorly known. MAP kinase phosphatase-1 (MKP-1) is an enzyme that limits the activity of pro-inflammatory MAP kinases p38 and JNK. In the present study, we discovered that dexamethasone down-regulates mPGES-1 expression in articular chondrocytes in an MKP-1 and p38 kinase dependent manner.MethodsPrimary human chondrocytes were isolated from cartilage samples obtained from osteoarthritis (OA) patients undergoing knee replacement surgery. Primary mouse chondrocytes were isolated from cartilage samples of MKP-1 deficient (knock-out, KO) and corresponding wild type (WT) mice. Expression of mPGES-1 and MKP-1 were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot, and MAP kinase phosphorylation by Western blot.ResultsDexamethasone inhibited the expression of mPGES-1 in primary human chondrocytes and in chondrocytes from wild type but not from MKP-1 deficient mice. Dexamethasone enhanced MKP-1 expression in chondrocytes from wild type mice as well as in primary human OA chondrocytes. Dexamethasone induced the dephosphorylation of both p38 and JNK, whereas mPGES-1 expression was downregulated by selective inhibitors of p38 only.ConclusionsThe results show that MKP-1 is a crucial mediator of pharmacological control of inflammatory mPGES-1 expression by glucocorticoids, and underline MKP-1 as a potential anti-inflammatory drug target.
       
  • Diallyl Trisulfide can induce fibroblast-like synovial apoptosis and has a
           therapeutic effect on collagen-induced arthritis in mice via blocking
           NF-κB and Wnt pathways
    • Abstract: Publication date: June 2019Source: International Immunopharmacology, Volume 71Author(s): Jing Jing Liang, Hao Ran Li, Yong Chen, Chen Zhang, Da Gui Chen, Zhi Chao Liang, Ye Qing Shi, Lan Ling Zhang, Lei Xin, Dong Bao Zhao BackgroundDiallyl Trisulfide (DATS) is an organosulfur compound extracted from garlic bulb, and exerts cardioprotective, anti-inflammatory, antioxidant, antimicrobial and anticancer effects. But its role in the pathogenesis of rheumatoid arthritis (RA) is unknown. Here we explored the influence of DATS on human fibroblast-like synoviocytes (FLS) isolated from RA patients and a mouse model of collagen-induced arthritis (CIA) and the underlying mechanism.MethodsRA-FLS were cultured and treated with different concentrations of DATS. The CCK8 assay was used to assess cell proliferation while cell apoptosis was detected by flow cytometry and western blot. The IL-8, IL-6 and IL-1β levels were determined using RT-qPCR and ELISA assay. The expression of proteins of the NF-κB and Wnt pathways were measured using western blot. Furthermore, the effect of DATS was also explored in vivo using the collagen-induced arthritis mouse model. The Th17/Treg pattern obtain from cells of spleen of collagen-induced arthritis mouse model was detected by flow cytometry.ResultsOur results showed that DATS could decrease cell viability and introduce apoptosis in RA-FLS. Furthermore, DATS significantly attenuated the production of key inflammatory cytokines induced by RA-FLS cells following treatment with tumor necrosis α (TNF-α) at a concentration of 100 μM or higher. This was due to its inhibitory effect on the NF-κB and Wnt pathway signaling in RA-FLS. Additionally, DATS decreased the production of inflammatory cytokines and regulated the immune function by restoring the balance between Th17 and Treg in CIA mouse model.ConclusionsIn conclusion, DATS may serve as a potential curative agent for RA.
       
  • Chronic arsenic exposure in drinking water interferes with the balances of
           T lymphocyte subpopulations as well as stimulates the functions of
           dendritic cells in vivo
    • Abstract: Publication date: June 2019Source: International Immunopharmacology, Volume 71Author(s): Lu Zhao, Shan Yang, Yuanyuan Guo, Guifan Sun, Bing Li The immunomodulatory properties of arsenic are nowadays supposed be associated with pathological injuries of this toxicant and the details have not been clarified. Our objective was to explore inflammation, differentiation of diverse T cell subsets, as well as the phenotypic molecules and functions of dendritic cells (DCs) by chronic arsenic exposure in vivo. We exposed different concentrations of arsenic (0, 0.1, 1 and 10 mg/L) in drinking water for 6 and 12 months in C57BL/6 mice. We first confirmed that low levels of arsenic induced excess inflammation evidenced by accumulation of macrophages and lymphocytes in bronchoalveolar lavage fluid (BALF), secretion of pro-inflammatory cytokine IL-1β in BALF and serum, as well as histological analysis. Flow cytometry analysis revealed that arsenic disturbed CD4/CD8 T-cell ratio in isolated pneumonocytes and splenocytes, as well as enhanced IFN-γ and reduced IL-4 in spleen. The mRNA expressions of transcription factors (T-bet, GATA3, ROR-γt) and cytokines (IFN-γ, IL-4, IL-10, IL-23, IL-22) showed the imbalanced Th1/Th2/Th17 differentiation in arsenic exposed lung and spleen. We further testified that arsenic enhanced the percentages of CD11c+ DCs, and promoted the expressions of antigen presentation molecule MHC II and cytokine IL-12, co-stimulatory molecules (CD86, CD80), and chemokine receptors (CCR7, CCR5) in vivo. Moreover, arsenic activated the expressions of immune-related MAPKs and NF-κB. Taken together, our study here demonstrated that chronic arsenic exposure could disrupt the immune homeostasis in vivo possibly by interfering with the differentiation of Th1/Th2/Th17 subsets as well as the function of DCs.
       
  • DNA methylation and transcriptome signature of the IL12B gene in
           ankylosing spondylitis
    • Abstract: Publication date: June 2019Source: International Immunopharmacology, Volume 71Author(s): Xu Zhang, Jincheng Lu, Zhipeng Pan, Yubo Ma, Rui Liu, Shuo Yang, Siyu Yang, Jiahui Dong, Xiaoyi Shi, Shengqian Xu, Faming Pan ObjectiveAnkylosing spondylitis (AS) is an autoimmune disease without a reliable biomarker. This study investigated the IL12B gene methylation as a robust marker by integrating DNA methylation and mRNA data.MethodsA two-stage design was used for methylome and transcriptome investigation. The first phase detected methylation level from 99 AS patients and 99 healthy controls (HCs) whilst the second phase measured mRNA level from 20 patients and 20 HCs. We conducted analysis of differential methylation sites and receiver operating characteristic (ROC) as well as mRNA level to verify methylation.ResultsWe investigated 37 methylation sites that were mapped to 2 CpG islands (IL12B-1 and IL12B-2). Compared with HCs, the two islands were hypermethylated (IL12B-1: P = 4.6 ∗ 10 ^ −4; IL12B-2: P = 1.3 ∗ 10 ^ −5) and the mRNA level was overexpressed (P = 0.004) in AS patients. The subgroup analysis results showed a significant hypermethylation of the two islands in B27 positive group (IL12B-1: P = 3.7 ∗ 10 ^ −4; IL12B-2: P = 3.7 ∗ 10 ^ −6) and in male patients (IL12B-1: P = 4.9 ∗ 10 ^ −4; IL12B-2: P = 7.2 ∗ 10 ^ −6). ROC results found that the IL12B-1 island had a sensitivity of 62.6% and a specificity of 66.7%, and the IL12B-2 had a sensitivity of 50.0% and a specificity of 77.7%.ConclusionDNA methylation and transcriptome signature of the IL12B gene can discriminate AS patients from HCs, and hypermethylation of the IL12B may contribute to the pathogenesis of AS.
       
  • A novel chalcone derivative, L2H17, ameliorates lipopolysaccharide-induced
           acute lung injury via upregulating HO-1 activity
    • Abstract: Publication date: June 2019Source: International Immunopharmacology, Volume 71Author(s): Yuting Lin, Danping Qiu, Lili Huang, Sangsang Zhang, Chenjian Song, Beibei Wang, Jianzhang Wu, Chengshui Chen BackgroundChalcone, a natural product, has a wide range of biological activities. L2H17, a chalcone derivative, was synthesized and screened in our previous study and exhibited excellent anti-inflammatory property in vitro. This study investigated the therapeutic potential of L2H17 on lipopolysaccharide (LPS)-induced acute lung injury (ALI) and the role of heme oxygenase-1 (HO-1).Materials and methodsAn ALI animal model was induced by LPS (10 mg/kg) intratracheal instillation. The effect of L2H17 on LPS-induced structural damage was determined using hematoxylin and eosin (HE) staining, and tissue edema extent was examined. Bronchoalveolar lavage fluid (BALF) was harvested to assess the levels of related cytokines by enzyme-linked immunosorbent assay (ELISA), and superoxide dismutase (SOD) activity was also assessed. HO-1 expression was determined using immunohistochemistry and western blotting. The effects of L2H17 on LPS stimulation in RAW 264.7 and the involvement of the HO-1 pathway were investigated.ResultsL2H17 alleviated the histopathological manifestations and tissue edema. Moreover, L2H17 decreased the production of pro-inflammatory factors in BALF and increased SOD activity. In vitro, L2H17 significantly reduced pro-inflammatory cytokine production. Additionally, L2H17 improved the expression of HO-1 in LPS-treated lung tissue and RAW 264.7. We also found that the inhibitory effect of L2H17 on the inflammatory responses was attenuated by an inhibitor of HO-1 activity, Tin protoporphyrin IX (SnPP).ConclusionOur data confirmed that L2H17 can exert protective effect on ALI in vitro and in vivo by inhibiting inflammatory responses and modulating the HO-1 pathway.
       
  • TGR5 agonist INT-777 mitigates inflammatory response in human
           endometriotic stromal cells: A therapeutic implication for endometriosis
    • Abstract: Publication date: June 2019Source: International Immunopharmacology, Volume 71Author(s): Dan Lyu, Ning Tang, Jianye Wang, Yan Zhang, Jianfang Chang, Zhitao Liu, Haiping Liu Endometriosis is a condition characterized by the presence of endometrial tissues outside the uterus. Endometriotic stromal cells (ESCs) are known to undergo regeneration and are linked to the causation of endometriosis. Activation of stromal cells by local inflammatory cytokines is proposed to be one of the mechanisms of endometriosis development. Takeda-G-protein-receptor-5 (TGR5) is a G protein-coupled bile acid receptor that plays multiple roles in various cells and tissues. In this study, we show that activation of TGR5 by its specific agonist, INT-777, protects ESCs from inflammation and oxidative stress induced by tumor necrosis factor-α (TNF-α). TGR5 is fairly expressed in cultured ESCs, and TNF-α treatment suppresses TGR5 expression. Activation of TGR5 by its synthetic agonist, INT-777, dramatically reduces the production of pro-inflammatory cytokines and adhesion molecules by TNF-α, including interleukin-6 (IL-6), interleukin-8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Moreover, INT-777 suppresses TNF-α-induced NADPH oxidase 4 (NOX4) expression and ameliorates cellular oxidative stress. Mechanistically, our findings demonstrate that INT-777 suppresses TNF-α-induced c-Jun N-terminal kinase (JNK) activation via suppression of p-JNK. INT-777 inhibits TNF-α-induced activation of the activator protein-1 (AP-1) pathway owing to its suppression of c-Jun and c-fos as well as transfected AP-1 promoter. INT-777 also inhibits nuclear factor-κB (NF-κB) activation as revealed by its suppression of TNF-α-induced nuclear p65 accumulation and NF-κB promoter. Collectively, our data indicate that activation of TGR5 by its agonist has protective effects against inflammation and reactive oxygen species (ROS) in cytokine-induced activation of ESCs. Therefore, INT-777 may have an implication in the clinical treatment of endometriosis.
       
  • Lipopolysaccharide-induced expression of astrocyte elevated gene-1
           promotes degeneration and inflammation of chondrocytes via activation of
           nuclear factor-κB signaling
    • Abstract: Publication date: June 2019Source: International Immunopharmacology, Volume 71Author(s): Zhong Qing, Jiumin Ye, Shufang Wu Osteoarthritis is an inflammatory disease characterized by joint degeneration and inflammation. Astrocyte elevated gene-1 (AEG-1) has been suggested as a novel inflammation-related factor in the pathological processes of various inflammatory diseases. To date, little is known about the role of AEG-1 in osteoarthritis. The aim of the present study was to explore the potential role of AEG-1 in the regulation of lipopolysaccharide-induced apoptosis and inflammation of chondrocytes. The results showed that AEG-1 expression was significantly upregulated in chondrocytes following exposure to lipopolysaccharide. Knockdown of AEG-1 increased the survival and decreased the expression of matrix metalloproteinases in chondrocytes treated with lipopolysaccharide. Moreover, silencing of AEG-1 restricted the lipopolysaccharide-induced production of proinflammatory cytokines. In contrast, AEG-1 overexpression caused opposite effects. Notably, we found that AEG-1 inhibition blocked the lipopolysaccharide-induced activation of nuclear factor-κB signaling through impeding the nuclear translocation of nuclear factor-κB p65 subunit. Additionally, inhibition of nuclear factor-κB partially reversed the AEG-1-mediated promotion of lipopolysaccharide-induced inflammatory injury in chondrocytes. In conclusion, our results demonstrate that inhibition of AEG-1 expression attenuates lipopolysaccharide-induced degeneration and inflammation of chondrocytes through suppressing the activation of nuclear factor-κB signaling. This work therefore highlights a potential role of AEG-1 in the pathogenesis of osteoarthritis, and indicates its potential as a therapeutic target.Graphical abstractUnlabelled Image
       
  • Epigenetic changes: An emerging potential pharmacological target in
           allergic rhinitis
    • Abstract: Publication date: June 2019Source: International Immunopharmacology, Volume 71Author(s): Jingpu Yang, Wei Zhong, Kai Xue, Zonggui Wang The importance of epigenetics has increased due to identification of its role in the pathophysiology of a number of diseases including allergic rhinitis. Amongst the different epigenetic changes in allergic retinitis, deacetylation of histone proteins by histone deacetylase (HDACs), hypermethylation of DNA by DNA methyltransferases (DNMT) and alteration in post-transcriptional process by the changes in the levels of miRNA are widely studied. Studies conducted related to allergic rhinitis have shown the elevation in the levels of HDAC1, 3 and 11 in the nasal epithelia and HDAC inhibitors have shown effectiveness in decreasing the symptoms of rhinitis. Their beneficial effects are attributed to restoration of the expression of TWIK-related potassium channel-1, correction of cytokine profile along with normalization of Th1/Th2 imbalance. Another epigenetic change due to increase in DNMT activity may induce DNA hypermethylation in CpG sites in the airway epithelial cells and CD4+ T-cells. The reduction in DNA methylation decreases allergic symptoms and normalizes the over-reactive immune system. Mechanistically, allergens may promote the hypermethylation in the promoter region of IFN-γ gene in CD4+ T cells via activation of ERK pathway to decrease the expression of IFN-γ. In allergic rhinitis patients, there is also a downregulation of certain miRNAs including miR-135a, miR-146a, miR-181a, miR-155 and upregulation of miRNA19a. This review discusses the studies describing the epigenetic changes taking place in the host cells in response to allergen along with possible mechanisms.
       
  • LncRNA analysis of lung tissues after hUC-MSCs and FTY720 treatment of
           lipopolysaccharide-induced acute lung injury in mouse models
    • Abstract: Publication date: June 2019Source: International Immunopharmacology, Volume 71Author(s): Xia Zhang, Huiying Liu, Shiyu Wang, Zihao Huang, Herong Wang, Wenkai Niu, Yanhong Qin, Changqing Bai, Gang Liu, Huipeng Chen Acute lung injury (ALI), a persistent lung inflammatory response syndrome, may evolve into acute respiratory distress syndrome (ARDS). Characterized by rapid onset, critical features, and a complex etiology, ALI remains a challenging critical respiratory disease. Recently, mesenchymal stem cells (MSCs) have provided a new solution for the treatment of ALI. We built a lipopolysaccharide (LPS)-induced ALI model in mice. After treatment with human umbilical cord mesenchymal stem cells (hUC-MSCs), FTY720, or a combination of hUC-MSCs and FTY207, the lung inflammatory response was apparently attenuated. To understand the mechanism underlying MSCs treatment of ALI at the genetic level, significant differentially expressed long non-coding RNAs (lncRNAs) between the treatment and model groups were analyzed using microarray technology. Moreover, genetic gene prediction, gene ontology (GO) analysis, pathway analysis, and transcription factor (TF) prediction were carried out. The results showed that a total of 66 lncRNAs were differentially expressed in all three treatment groups, including 8 up-regulated and 58 down-regulated lncRNAs. LncRNA A_30_P01029806 and A_30_P01029194, which were down-regulated, were involved in the signaling pathways closely related to ALI. Through further TF analysis, we identified several significant TFs which lay a foundation for revealing the mechanism underlying lncRNAs treatment of ALI. LncRNA A_30_P01029806 and A_30_P01029194 may serve as candidate biomarkers in the diagnosis and treatment of ALI.
       
  • Hydrogen gas inhalation attenuates sepsis-induced liver injury in a
           FUNDC1-dependent manner
    • Abstract: Publication date: June 2019Source: International Immunopharmacology, Volume 71Author(s): Mengying Yan, Yang Yu, Xing Mao, Jingcheng Feng, Yanyan Wang, Hongguang Chen, Keliang Xie, Yonghao Yu Sepsis-induced hepatic dysfunction is considered as an independent risk factor of multiple organ dysfunction syndrome (MODS) and death. Mitophagy, a selective form of autophagy, plays a major role in sepsis-induced organ damage. We have demonstrated that hydrogen gas (H2), a selective antioxidant, exerts protective effects in septic mice. Here, we hypothesize that the therapeutic effects of H2 on septic animals with liver damages may be exerted through regulation of the Fun14 domain-containing protein 1 (FUDNC1)-induced mitophagy pathway. Male C57BL/6J mice were subjected to sham or cecal ligation and puncture (CLP) operation and treated with 2% H2 gas inhalation for 3 h starting at 1 h after sham or CLP surgery. To verify the role of FUNDC1, the cell-penetrating peptide P (NH2-GRKKRRQRRRPQDYESDDESYEVLDLTEY-COOH) (1 mg/kg) that functions as a FUNDC1 inhibitor was intraperitoneally injected into mice 24 h before the sham or CLP operation. To evaluate the severity of septic liver injury, the 7-day survival rate, liver histopathologic score, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, respiration control ratio (RCR), and FUDNC1, P-18-FUDNC1, P62, LC3B-II, Tim23, and caspase-1 levels were evaluated after the sham or CLP operation. The results demonstrated that 2% H2 gas inhalation resulted in an increase in the 7-day survival rate, ALT and AST levels, RCR, and P62 and LC3B-II expression but decreased the histological score and FUDNC1, P-18-FUDNC1, Tim23, and caspase-1 levels after sepsis. However, no significant differences were reported between the CLP + peptide P and CLP + H2 + peptide P groups. These observations indicate that 2% H2 gas inhalation for 3 h may serve as an effective therapeutic strategy for sepsis-induced liver injury through the regulation of FUNDC1-dependent mitophagy.
       
  • Methane ameliorates post-operative cognitive dysfunction by inhibiting
           microglia NF-κB/MAPKs pathway and promoting IL-10 expression in aged mice
           
    • Abstract: Publication date: June 2019Source: International Immunopharmacology, Volume 71Author(s): Dan Zhang, Na Li, Yuanyuan Wang, Wenbin Lu, Yongyan Zhang, Yuanjie Chen, Xiaoming Deng, Xiya Yu Postoperative cognitive dysfunction (POCD) is one of the most common complications after surgery. Accumulating evidence suggests that postoperative neuro-inflammation plays a critical role in the mechanism of POCD. Recently, exogenous methane is reported to have anti-inflammatory properties and play a neuro-protective role in acute carbon monoxide poisoning injury. Therefore, we investigated the protective effect of methane on a POCD model induced by abdominal surgery and its underlying mechanism in aged mice. Methane-rich saline (MS) or normal saline (NS) (16 ml/kg) was injected intraperitoneally 30 min after the abdominal surgery. The result showed that methane attenuated spatial memory loss in Morris water maze (MWM) with decreasing pro-inflammatory cytokines production and activation of microglia in hippocampus after surgery. Meanwhile, methane treatment suppressed lipopolysaccharide (LPS)-stimulated phosphorylation of MAPKs pathways and its downstream target TNF-α and IL-6 in BV2 cells. Moreover, methane increased expression of IL-10 in the hippocampus 24 h after surgery, and blockade of IL-10 repressed the protective effect of methane on the cognitive impairments observed in MWM test, decreased microglial activation and the pro-inflammatory cytokine in plasma and hippocampal. Blockade of IL-10 abrogated the suppression effect of methane on the pro-inflammatory cytokine production and phosphorylation of NF-κB and p38MAPK both in hippocampus and in BV2 cells. In conclusion, our study suggests exogenous methane could be a novel agent for the therapy of POCD through its anti-inflammation properties.
       
  • Comparison of anti-atopic dermatitis activities between DHMEQ and
           tacrolimus ointments in mouse model without stratum corneum
    • Abstract: Publication date: June 2019Source: International Immunopharmacology, Volume 71Author(s): Huan He, Xiaoxiao Gao, Xiaomin Wang, Xin Li, Xiaoxue Jiang, Zhehui Xie, Ke Ma, Jun Ma, Kazuo Umezawa, Yuyang Zhang This study is aimed to further investigate the anti-atopic dermatitis (AD) activities of dehydroxymethylepoxyquinomicin (DHMEQ) ointment and compare its effect with that of tacrolimus ointment based on the previous study that DHMEQ improves AD-like lesions. AD were induced by 2,4-dinitroclilorobenzene/oxazolone (DNCB/OX) repeatedly on the ears of BABL/C mice while medical tape was additionally used to disrupt stratum corneum in order to exacerbate the lesions. The mice were randomly divided into groups, which are normal, vehicle, DHMEQ (0.1%) and tacrolimus (0.1%). Those in the last two groups were externally applied with DHMEQ ointment and tacrolimus ointment, respectively. The results showed that both of them significantly improved dermatitis symptoms of DNCB/OX-induced AD-like lesions, such as redness, itching, weeping, scaling and thickening of the skin, while reducing epidermis thickness, dermis thickness and the number of mast cells as well, which were examined histopathologically. In contrast with DHMEQ, tacrolimus led to a significant decrease in body weight after long-term application. Both DHMEQ and tacrolimus suppress DNCB-induced increase of serum total IgE and attenuate expression of inflammatory factors IL-4, IL-6, IL-13, IL-1β and interferon (IFN)-γ in the disrupted ear tissues. On the other hand, the mice applied with tacrolimus became obviously irritable, jumping up and down, and inflammatory exudation on the lesioned-skin surface of the mice was remarkably observed. Contrary to the side effects made by tacrolimus, DHMEQ didn't cause any adverse stimulus response. As a conclusion, DHMEQ is safer, milder and more suitable for long-term use than tacrolimus for the treatment of AD-like lesions.
       
  • Thalidomide ameliorate graft chronic rejection in an allogenic kidney
           transplant model
    • Abstract: Publication date: June 2019Source: International Immunopharmacology, Volume 71Author(s): Yan Zhang, Yu Yang, Xianduo Li, Dongdong Chen, Guanbao Tang, Tongyi Men Chronic T cell mediated rejection (TCMR), which is characterized by infiltration of the interstitium by T cells and macrophages, still remains a major barrier to the long-term survival of kidney transplantation. Our recent report indicated that thalidomide can attenuate graft arteriosclerosis in an aortic transplant model. In this study, we investigated the effect of thalidomide on chronic TCMR in a rat model of kidney transplantation.Fischer or Lewis kidney allografts were transplanted into Lewis recipient rats. After kidney transplantation, recipient rats were divided into 3 groups: the isograft (Iso) group, allograft (Allo) group, and thalidomide (Tha) group. Rats were sacrificed at 8 weeks after kidney transplantation, and blood and kidney samples were collected. Serum concentrations of creatinine (SCr),interleukin (IL)-2, IL-6, IL-17, and TNF-α in recipients were determined, and flow cytometry was used to detect the percentages of CD4+CD25+, CD4+ Foxp3+and CD4+Th17+ cell subsets in the peripheral blood. Grafts were procured for histopathological examination, and the expressions of α-SMA, transforming growth-β1 (TGF-β1), and VEGF in kidney grafts were investigated using Western blot. Thalidomide treatment significantly ameliorated chronic rejection, reduced renal allograft tissue damage, and decreased serum creatinine levels. Attenuation of chronic TCMR was due to the prohibited production of inflammatory cytokines, altered distribution of the CD4+ CD25+ FoxP3+ regulatory T (Treg) and CD4+ Th17+ cells in the peripheral blood, and decreased expression of TGF-β1, α-SMA, and VEGF in the kidney graft. These results demonstrated that thalidomide could effectively ameliorate chronic TCMR in a rat kidney transplant model.
       
  • Isosalvianolic acid C-induced pseudo-allergic reactions via the mast cell
           specific receptor MRGPRX2
    • Abstract: Publication date: June 2019Source: International Immunopharmacology, Volume 71Author(s): Yuanyuan Lin, Jue Wang, Yajing Hou, Jia Fu, Di Wei, Qianqian Jia, Yanni Lv, Cheng Wang, Shengli Han, Langchong He Pseudo-allergic reactions occurred in patients administered drugs for the first time, seriously threaten man's survival. Due to the frequent reports of pseudo-allergic reactions to Danshen injection, in our previous study, isosalvianolic acid C in Danshen injection was found to trigger off mast cell degranulation. However, the direct involvement and the mechanisms underlying pseudo-allergic reactions have not been elucidated. In this study, the pseudo-allergic reactions induced by isosalvianolic acid C were confirmed by an ear swelling assay, a hindpaw swelling and extravasation assay in vivo and mast cell degranulation assays in vitro. We also evaluated whether the pseudo-allergic effect is related to MRGPRX2, Isosalvianolic acid C induced Ca2+ mobilization was verified as MRGPRX2-related by Ca2+ imaging using mouse peritoneal mast cells (both wild-type and MrgprB2 knockout mice), MRGPRX2-expressing HEK293 and MrgprB2-expressing HEK293 cells. MRGPRX2-related pseudo-allergic reactions induced by Isosalvianolic acid C were further confirmed by MrgprB2 knockout mice and MRGPRX2 knockdown mast cells both exhibited reduced isosalvianolic acid C-induced pseudo-allergic effects. Furthermore, both the frontal analysis and molecular docking assays showed that isosalvianolic acid C has a considerable affinity with MRGPRX2. Based on the above experiments, the western blot analyses were conducted, the results indicated that isosalvianolic acid C induced Ca2+ mobilization and degranulation via the activation of PLC-γ and IP3R, and releasing chemokines via the activation of PLC-γ, PKC and P38. This study should alarm many clinicians that medicines containing isosalvianolic acid C might induce pseudo-allergic reactions, and it may provide guidance on safe dosage of these medicines in the process of production and use.Graphical abstractIn this study, we first identified and showed that Isosalvianolic acid C induces pseudo-allergic reactions via the mast cell specific receptor MRGPRX2.Unlabelled Image
       
  • Triptolide ameliorates lupus via the induction of miR-125a-5p mediating
           Treg upregulation
    • Abstract: Publication date: June 2019Source: International Immunopharmacology, Volume 71Author(s): Xia Zhao, Xiaojun Tang, Qing Yan, Hua Song, Zutong Li, Dandan Wang, Hongwei Chen, Lingyun Sun Triptolide is a biologically active component of the Chinese antirheumatic herbal remedy Tripterygium wilfordii Hook F, which has been shown to be effective in treating murine lupus. However, its immunological mechanisms are poorly understood. Regulatory T cells (Treg) are pivotal for maintaining peripheral self-tolerance and controlling autoimmunity. This study was undertaken to examine the therapeutic effect of triptolide in lupus mice and the related molecular mechanisms. Our results showed that triptolide treatment ameliorated serum anti-dsDNA, proteinuria and renal histopathologic assessment in MRL/lpr mice, induced the miR-125a-5p expression and enhanced the proportion of Treg in vivo. In vitro, triptolide upregulated the proportion of Treg and the miR-125a-5p expression. Down-regulation of the miR-125a-5p expression reversed the effect of triptolide on Treg. In conclusion, triptolide could induce Treg and the miR-125a-5p expression in vivo and in vitro. Inhibiting the effect of miR-125a-5p could counteract the effect of triptolide on inducing Treg. The study has strong implications for the therapeutic applications of triptolide in systemic lupus erythematosus.
       
  • NLRX1 alleviates lipopolysaccharide-induced apoptosis and inflammation in
           chondrocytes by suppressing the activation of NF-κB signaling
    • Abstract: Publication date: June 2019Source: International Immunopharmacology, Volume 71Author(s): Ding Ma, Yangxue Zhao, Jiang She, Yandong Zhu, Yu Zhao, Liang Liu, Yingang Zhang Osteoarthritis (OA) is a chronic debilitating disease characterized by joint degeneration. Excessive chondrocyte apoptosis and inflammation contributes to articular cartilage destruction in OA pathology. Nucleotide-binding oligomerization domain (NOD)-like receptor X1 (NLRX1) has emerged as a critical regulator of inflammation that participates in the pathology of diverse diseases. To date, little is known about the role of NLRX1 in OA. In the present study, we aimed to explore the function of NLRX1 in lipopolysaccharide (LPS)-induced injury in chondrocytes, an in vitro model of OA. NLRX1 mRNA was detected by quantitative polymerase chain reaction (qPCR) analysis. Protein expression of NLRX1, phosphorylated IκB kinase β (IKKβ), and phosphorylated nuclear factor-κB (NF-κB) p65 were examined by western blot. Cell viability was assessed by the MTT assay. Cell apoptosis was evaluated by measuring caspase-3 activity. Cytokine release was assessed by enzyme-linked immunosorbent assay (ELISA). NF-κB signaling activation was analyzed with a luciferase reporter assay. Herein, our results revealed that NLRX1 expression was markedly decreased in LPS-treated chondrocytes. Functional experiments demonstrated that NLRX1 overexpression significantly improved cell viability and attenuated LPS-treated chondrocyte apoptosis and inflammation, while NLRX1 silencing caused the opposite effects. Moreover, our results showed that NLRX1 regulated LPS-induced NF-κB signaling activation. Notably, NF-κB signaling inhibition significantly reversed the NLRX1-knockdown-mediated enhanced effects on LPS-induced apoptosis and inflammation. Overall, these results demonstrate that NLRX1 alleviates LPS-induced apoptosis and inflammation in chondrocytes by negatively regulating NF-κB signaling, results that indicate an anti-inflammatory role for NLRX1 in OA. Our findings suggest that NLRX1 may serve as a potential therapeutic target for OA.Graphical abstractUnlabelled Image
       
  • Berberine suppresses mast cell-mediated allergic responses via regulating
           FcɛRI-mediated and MAPK signaling
    • Abstract: Publication date: June 2019Source: International Immunopharmacology, Volume 71Author(s): Shuilian Fu, Saihong Ni, Danni Wang, Meng Fu, Tie Hong The anti-allergic effect of berberine was evaluated in cellular and animal models of allergic responses. In this study, the results of the in vitro model of immunoglobulin (Ig) E-mediated mast cell degranulation showed that berberine significantly inhibited the release of β-hexosaminidase (β-HEX), histamine, IL-4 and TNF-α in rat basophilic leukemia cells (RBL-2H3 cells). Pretreatment with berberine prevented morphological changes in IgE-stimulated RBL-2H3 cells such as the recovery of an elongated shape. Pretreatment with berberine also suppressed the phosphorylation of antigen-induced Lyn, Syk, and Gab2, thus suppressing the downstream MAPK pathways. In the in vivo model of allergic responses, administration of berberine inhibited passive cutaneous anaphylaxis (PCA) in mice. The above results indicate berberine could suppress mast cell activation and allergic responses.
       
  • The protective effect of oleanolic acid on NMDA-induced MLE-12 cells
           apoptosis and lung injury in mice by activating SIRT1 and reducing NF-κB
           acetylation
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Xiang-Ping Peng, Xiao-Hong Li, Yang Li, Xiao-Ting Huang, Zi-Qiang Luo Overactivation of the N-methyl-d-aspartate (NMDA) receptor promotes oxidative stress, aggravates the inflammatory response and induces excitotoxic lung injury. NMDA is a synthetic agonist that selectively activates the NMDA receptor. Oleanolic acid (OA) is a natural anti-inflammatory and antioxidant compound. This study investigated the effect and possible mechanism of OA on NMDA-induced acute lung injury (ALI) in mice. OA pretreatment alleviated NMDA-induced histological lung changes and ameliorated pulmonary oedema and pulmonary permeability. At the same time, OA inhibited inflammatory cell infiltration and decreased the levels of tumour necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1β in the lung and bronchoalveolar lavage fluid (BALF). OA markedly decreased malondialdehyde (MDA) production and increased the superoxide dismutase (SOD) and glutathione (GSH) contents of the lung in vivo. Meanwhile, we first found that NMDA increased LDH activity and decreased cell viability, and induced oxidative stress and apoptosis in mouse lung epithelial (MLE)-12 cells. By employing SRT1720 and sirtinol, the activator and inhibitor of sirtuin 1 (SIRT1), we found that SRT1720 partially eliminated the increase in ROS,and sirtinol further promoted the increase in ROS caused by NMDA. OA increased MLE-12 cells viability and attenuated oxidative stress after NMDA challenge in vitro. OA suppressed NMDA-induced MLE-12 cells apoptosis, while sirtinol inhibited the effect of OA. In addition, OA significantly upregulated the levels of SIRT1, nuclear-related factor 2(Nrf2) and Bcl-2 protein and downregulated the levels of acetylated nuclear factor-kappa B (NF-κB), NLRP3 and Bax protein. In conclusion, OA attenuated NMDA-induced excitotoxic lung injury, potentially through its anti-inflammatory, antioxidative stress and anti-apoptotic effects. The mechanism may be related to activating SIRT1 and reducing NF-κB acetylation.
       
  • Gallic acid alleviates nasal inflammation via activation of Th1 and
           inhibition of Th2 and Th17 in a mouse model of allergic rhinitis
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Yanjing Fan, Chun Hua Piao, Eunjin Hyeon, Sun Young Jung, Ji-Eun Eom, Hee Soon Shin, Chang Ho Song, Ok Hee Chai Allergic rhinitis (AR) is an allergic nasal disease characterized by nasal obstruction, rhinorrhea, sneezing, and itching. Type 1 helper T cells (Th1)/type 2 helper T cells (Th2) imbalance has been identified as an important immunological mechanism of AR. In addition, up-regulation of type 17 helper T cells (Th17) also increase the risk of developing AR. Gallic acid (3, 4, 5-trihydroxybenzoic acid, GA), a polyphenol natural product, is obtained from various herbs, red wine, and green tea. It is known to have diverse biological effects such as anti-oxidation, anti-inflammation, anti-microbial and anti-cancer. In the present study, the effect of GA on airway inflammation and expression of Th1, Th2 and Th17 cytokines in an ovalbumin (OVA)-induced AR mouse model were investigated. GA alleviated the nasal allergic symptoms, reduced the thickness of nasal mucosa, attenuated goblet cell hyperplasia and eosinophil cell infiltration in the nasal mucosa, decreased the levels of interleukin (IL)-4, IL-5, IL-13 and IL-17 in nasal lavage fluid (NALF), and diminished the levels of OVA-specific IgE, OVA-specific IgG1 and OVA-specific IgG2a in serum. However, GA increased the expression of interferon-gamma and IL-12 in NALF. Taken together, it suggests that GA may be used as a therapeutic agent for AR.
       
  • Glycyrrhizin administration ameliorates Streptococcus
           aureus-
    induced acute lung injury
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Li Yao, Tianle Sun Streptococcus aureus (S. aureus)-induced acute lung injury (ALI) has a high incidence of mortality clinically. Glycyrrhizin (GL) is a traditional Chinese medicine for anti-inflammatory. However, the role of GL in S. aureus-induced ALI has not previously been elucidated.GL (25 mg/kg i.p.) administration exerts potent anti-inflammatory effect in this model. GL administration significantly alleviated inflammation via reduction of multiple cytokines (serum and lung tissue IL-6, TNF-α, IL-8, IL-1β and HMGB1) and immune cells (lung tissue neutrophil and macrophage infiltration). Additionally, we measured the signaling pathways (NF-kB and MARKs) and inflammasome dependent pyroptosis. The results suggest that GL inhibits NF-kB, p38/ERK pathways and pyroptosis. Furthermore, we used different inhibitors to treat infected-A549 cells and found that BMS-582949 (a p38 inhibitor) is the most effective inhibitor for inhibiting pro-inflammatory cytokines (IL-6, TNF-α and IL-1β) production, which suggests that p38 signaling pathway might be the main pathway for S. aureus-induced inflammation.Collectively, the data demonstrates that GL could mitigate inflammation after S. aureus infection.
       
  • Chimeric antigen receptor T cell therapy and other therapeutics for
           malignancies: Combination and opportunity
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Luyao Wang, Ruixue Yao, Lifa Zhang, Chuanbo Fan, Leina Ma, Jia Liu Chimeric antigen receptor T (CAR-T) cell therapy provides possibility for the treatment of malignancies since clinical trials have shown that CAR-T therapy has a significant anti-tumor effect. Although many efforts have been made to improve the efficacy and reduce the side effects of CAR-T therapy, there are still many problems to solve. With the rapid development of this field, combination immunotherapy has been proved to improve the efficacy of CAR-T therapy. Studies have shown that radiotherapy, chemotherapy, oncolytic virotherapy, BTK inhibitors and immune checkpoint blockade-based therapy may further enhance the efficacy of CAR-T therapy while CRISPR/Cas9 technology and IL-1 blockade may improve the safety. In this review, we summarized the advantages and the mechanisms of the combination immunotherapy based on CAR-T cell therapy.
       
  • Tanshinone IIA harmonizes the crosstalk of autophagy and polarization in
           macrophages via miR-375/KLF4 pathway to attenuate atherosclerosis
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Wenna Chen, Ximing Li, Shengnan Guo, Nan Song, Junyan Wang, Lianqun Jia, Aisong Zhu Macrophages play a pivotal role in destabilizing atherosclerotic plaque. The diverse phenotypes and complex autophagy in macrophage are observed in atherosclerotic lesions. Tanshinone IIA (TNA) is known as the major component extracted from the root of Chinese herb Salvia miltiorrhiza, used for treatment of cardiovascular diseases. However, the therapeutic mechanism of TNA is not clear yet. In this study, we identified inflammation-related gene expression by microarray in atherosclerotic plaques in ApoE knockout mice fed with high fat diet and found miR-375 was one of the significantly high expressed microRNAs compared with wild type mice and TNA treated mice. Then we compared the levels of proteins related to the signal pathway of autophagy, and the phenotype of macrophages in atherosclerotic plaques ex vivo. We predicted KLF4 might be the key target of miR-375 that mediated the crosstalk between autophagy and polarization by TNA. Furthermore, we detected the expression of signal pathway in ox-LDL induced macrophages after treatment with TNA in vitro to verify this predict. The results suggest TNA could activate KLF4 and enhance autophagy as well as M2 polarization of macrophages by inhibiting miR-375 to Attenuate Atherosclerosis.
       
  • Pre-activation of TLR3 enhances the therapeutic effect of BMMSCs through
           regulation the intestinal HIF-2α signaling pathway and balance of NKB
           cells in experimental alcoholic liver injury
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Lichao Ge, Dazhi Chen, Wenkai Chen, Chao Cai, Ying Tao, Shasha Ye, Zhuo Lin, Xiaodong Wang, Ji Li, Lanman Xu, Yongping Chen Increased intestinal permeability and immune disorder are important mechanisms of alcoholic liver disease (ALD). Recent evidences suggest bone marrow derived mesenchymal stem cells (BMMSCs) have protective effects on end-stage liver disease and intestinal barrier injury. Moreover, the activation of toll-like receptor 3 (TLR3) has been shown enhancing therapeutic effects of BMMSCs in inflammatory bowel disease (IBD). However, the mechanism remains unclear. In current study, chronic-binge alcohol abuse model was employed to investigate the therapeutic effects of BMMSCs and BMMSCs pre-activated with TLR3 (P-BMMSCs) on alcohol-induced liver and intestine damage. C57BL/6 mice were divided into four groups with normal control, alcohol-fed model, alcohol-fed model with BMMSCs treatment and alcohol-fed model with P-BMMSCs treatment. Alcohol-fed mice were fed Lieber-DeCali diet containing 5% alcohol for four weeks and given alcohol intragastrically on the 28th day, but control group were fed isocaloric diet. BMMSCs and P-BMMSCs were injected into the treatment group three times. Results showed alcohol diet causing significant damage to intestinal barrier and liver. These were reversed by the treatment of BMMSCs, especially P-BMMSCs. Moreover, alcohol increased the expression of intestinal HIF-2α, the proportion of NKB cells and the level of serum IL-18, while BMMSCs or P-BMMSCs reduced these factors. In conclusion, BMMSCs, especially TLR3 pre-activated BMMSCs could be used to protect alcohol-induced intestine and liver injury.
       
  • Recombinant plasmids containing CpG with porcine host defense peptides
           (PR-39/pBD-1) modulates the innate and adaptive intestinal immune
           responses (including maternal-derived) in piglets
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Shuxia Zhang, Haiming Cai, Ding Cao, Jinbo Deng, Junhao Jia, Jiaoqing Li, Feiping Ming, Peijing Zhao, Miaopeng Ma, Qianyi Liang, Min Zeng, Linghua Zhang CpG oligodeoxynucleotides (CpG-ODN) is an immunoenhancer, which is composed of unmethylated cytosine and guanine. Host Defense Peptides (HDPs) are small molecule polypeptides with various immunological activities that have been shown to induce a stronger innate immune response in piglets with synthetic CpG-ODN. Therefore, combination of CpG-ODN and HDPs was expected to be a novel immunoadjuvant with high efficiency, low toxicity and great potential. However, cost of synthetic HDPs or CpG-ODN is too high to be advantageous for animal farming. In this study, in order to improve the immune function of vaccine and reduce cost, a series of recombinant plasmids (containing HDPs gene (PR-39/pBD-1) and different numbers of CpG motifs) were constructed. In vitro, porcine lymphocytes were stimulated by recombinant plasmids to verify the immunostimulatory function of recombinant plasmids. In vivo, recombinant plasmids were used to immunize piglets with Enterotoxigenic Escherichia coli (ETEC) vaccine to analyze effects of recombinant plasmids on the mucosal immune responses. In addition, dosage screening and capability of maternal antibody responses were also investigated. Our results showed that recombinant plasmids had strong adjuvant effects especially the plasmid pVAX49-PR-39 and pVAX49-pBD-1. Moreover, there was no diarrhea in piglets using pVAX49-PR-39 or pVAX49-pBD-1 as adjuvants. These findings suggested that recombinant plasmids (containing PR-39/pBD-1 and CpG) as adjuvants of vaccines could enhance immune stimulation better than HDPs or CpG alone. It has a good protective effect on maintaining health of newborn piglets. Among them, both plasmids pVAX49-PR-39 and pVAX49-pBD-1 could be used as effective vaccine adjuvants for piglets.
       
  • M1 and M2 macrophage polarization and potentially therapeutic naturally
           occurring compounds
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Youhan Wang, Wanli Smith, Dingjun Hao, Baorong He, Lingbo Kong Macrophages, as crucial cellular components of innate immunity, are characterized by possessing high plasticity and an abnormal ability to differentiate in response to numerous stimuli. Given this, macrophages show extreme heterogeneity under both physiological and pathological conditions. Typically, macrophages can be polarized into classically activated macrophages (M1) and alternatively activated macrophages (M2) depending on their environment. The relative functions of these two subtypes are almost exactly opposed to one another. Recent studies have suggested that some naturally occurring compounds can exert regulatory effects on the progression of macrophage polarization, which implies that they could be promising therapeutic tools to treat relevant diseases. Therefore, in our current review, we summarize recent studies on several naturally occurring compounds that may possess the ability to regulate macrophage polarization and explore the associated molecular mechanisms.
       
  • Two-hit model of postintensive care syndrome induced by lipopolysaccharide
           challenge and subsequent chronic unpredictable stress in mice
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Mingjie Mao, Shuming Li, Manman Zong, Lili Qiu, Jiaojiao Yang, Jiangyan Xia, Jianjun Yang, Muhuo Ji Postintensive care syndrome (PICS) is defined as a new or worsening impairment in cognition, mental health, and physical function after critical illness. However, there is still a lack of a clinically relevant animal model. Thus, development of a PICS model is essential for understanding the mechanism underlying PICS and screening treatment methods for this neuropsychiatric disorder. The purpose of this study was to establish a clinically relevant PICS model based on the two-hit concept, in which lipopolysaccharide (LPS, 3 mg/kg) injection was served as the first hit and subsequent modified chronic unpredictable stress as the second hit. In order to pharmacologically verify the proposed model of PICS, we studied the effectiveness of fluoxetine to reverse the behavioral and molecular abnormalities in this model. In the present study, body- and adrenal weight changes proved our model was effective, as reflected by body weight loss, increased adrenals weight, and a significantly increased level of plasma corticosterone. Moreover, our PICS model displayed reproducible anxiety- and depression like behavior and cognitive impairments. Neurobiological investigations revealed a significant up-regulation of the microglial marker CD68 and pro-inflammatory cytokine IL-6 in the hippocampus of stressed mice. Notably, chronic treatment with fluoxetine for three weeks reversed most of the affected parameters. In summary, we believe that we have developed a new model of PICS that is clinically relevant, which could advance the mechanism research and the development of therapeutic strategies.
       
  • Protective effects of levo-tetrahydropalmatine on hepatic
           ischemia/reperfusion injury are mediated by inhibition of the ERK/NF-κB
           pathway
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Qiang Yu, Liwei Wu, Tong Liu, Sainan Li, Jiao Feng, Yuqing Mao, Xiaoming Fan, Chuanyong Guo, Jianye Wu BackgroundHepatic ischemia/reperfusion (IR) injury is a common medical phenomenon that occurs during a number of clinical conditions, such as liver transplantation, severe injuries, and shock. In our study, we determined the protective functions of levo-tetrahydropalmatine (L-THP) on hepatic IR injury in mice by inhibiting the ERK/NF-κB signaling pathway.MethodBALB/c mice were randomly divided into six groups as follows: normal control (NC); sham; L-THP (40 mg/kg); IR; L-THP (20 mg/kg) + IR; and L-THP (40 mg/kg) + IR. Liver tissues and sera were collected at three time points after reperfusion (2, 8, and 24 h). The liver enzyme, inflammatory factor, and other protein levels in the serum and liver tissues were detected.ResultsL-THP pretreatment alleviated hepatocyte injury caused by IR and reduced the production of proinflammatory cytokines, such as IL-6 and TNF-α. Furthermore, L-THP could inhibit the ERK/NF-κB signaling pathway to attenuate hepatocyte apoptosis and autophagy. And the protective effect of L-THP is positively correlated with its dose.ConclusionL-THP protects the liver from IR injury by inhibiting the release of inflammatory factors and alleviating liver cell apoptosis and autophagy. The protective functions of L-THP may be partly based on the downregulation of the ERK/NF-κB pathway.
       
  • T-cells interact with B cells, dendritic cells, and fibroblast-like
           synoviocytes as hub-like key cells in rheumatoid arthritis
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Xiao-Xi Hu, Yu-jing Wu, Jing Zhang, Wei Wei Rheumatoid arthritis (RA) is a chronic inflammatory synovitis-based systemic disease characterized by invasive joint inflammation and synovial hyperplasia, which can lead to arthrentasis and defunctionalization. Previous research has shown that T cells, B cells, dendritic cells (DCs), and fibroblast-like synoviocytes (FLSs) play vital roles in the regulation of RA. Both T follicular helper (Tfh) cells and helper T (Th) 17 cells play immunomodulatory roles in RA. Moreover, interleukin-23 (IL-23), and IL-17 are vital to the pathogenesis of RA. T cells behave as a hub, in that B cells, DCs, and FLSs can interact with T cells to inhibit their activation and interfere with the process of RA. T cells cooperate with B cells, DCs, and FLSs to maintain the stability of the immune system under physiological conditions. However, under pathological conditions, the balance is disrupted, and the interaction of T cells with other cells may intensify disease progression. This review focuses on the interaction of T cells with B cells, DCs, and FLSs in different tissues and organs of RA patients and animal models, and highlight that the interplay between immune cells may underline the unique function of T cells and the application prospect of targeting T cell treatment for RA.
       
  • Mast cell-mediated hypersensitivity to fluoroquinolone is MRGPRX2
           dependent
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Rui Liu, Shiling Hu, Yongjing Zhang, Delu Che, Jiao Cao, Jue Wang, Tingting Zhao, Qianqian Jia, Nan Wang, Tao Zhang Fluoroquinolones trigger anaphylaxis during clinical applications, affecting the safety of their administration. Mast cells are immune cells that act as sentinels during host defenses, mediating hypersensitivity and anaphylactic reactions. Mas-related G protein-coupled receptor X2 (MRGPRX2) is a mast cell-specific receptor that mediates cell degranulation in anaphylactic reactions. In this study, the mechanism underpinning the anaphylactic reactions caused by fluoroquinolones was investigated. Hypersensitivity was assessed through hindpaw swelling, tissue fluid leakage assays, in vivo and body temperature measurements assay in vivo, and cell calcium mobilization assays, and mast cell degranulation assays in vitro. Mast cell-deficient W-sash c-kit mutant KitW-sh/W-sh mice and MrgprB2 (the orthologous receptor of MRGPRX2 in mice) knockout mice exhibited reduced fluoroquinolone-induced anaphylactic effects. Fluoroquinolones activated mast cells in a dose-dependent manner and reduced degranulation was observed following MRGPRX2 silencing. These results reveal that fluoroquinolone-induced anaphylactic reactions are mediated by mast cells through MRGPRX2.Graphical abstractUnlabelled Image
       
  • Cell wall fraction of Mycobacterium indicus pranii shows
           potential Th1 adjuvant activity
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Mohd Saqib, Rahul Khatri, Bindu Singh, Ananya Gupta, Sangeeta Bhaskar Very few adjuvants inducing Th1 immune response have been developed and are under clinical investigation. Hence, there is the need to find an adjuvant that elicits strong Th1 immune response which should be safe when injected in the host along with vaccines. Mycobacterium indicus pranii (MIP), a non-pathogenic vaccine candidate, has shown strong immunomodulatory activity in leprosy/tuberculosis/cancer and in genital warts patients where its administration shifted the host immune response towards Th1 type. These findings prompted us to study the components of MIP in detail for their Th1 inducing property. Since mycobacterial cell wall is very rich in immunostimulatory components and is known to play important role in immune modulation, we investigated the activity of MIP cell wall using Ovalbumin antigen (OVA) as model antigen. ‘Whole cell wall’ (CW) and ‘aqueous soluble cell wall fractions’ (ACW) induced significant Th1 immune response while ‘cell wall skeleton’ (CWS) induced strong Th2 type of immune response. Finally, functional activity of fractions having Th1 inducing activity was evaluated in mouse model of melanoma. CW demonstrated significant anti-tumor activity similar to whole MIP. Anti-tumor activity of CW could be correlated with enhanced tumor antigen specific Th1 immune response observed in tumor draining lymph nodes.
       
  • Indirubin-3′-monoxime prevents aberrant activation of GSK-3β/NF-κB and
           alleviates high fat-high fructose induced Aβ-aggregation, gliosis and
           apoptosis in mice brain
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): C. Sathiya Priya, R. Vidhya, K. Kalpana, C.V. Anuradha Deciphering the molecular mechanisms of amyloid pathology and glial cell-mediated neuroinflammation, offers a novel avenue for therapeutic intervention against neurodegeneration. Recent findings demonstrate a crucial link between activation of glycogen synthase kinase-3β (GSK-3β), amyloid deposition and a neuroinflammatory state. However, studies demonstrating the pharmacological effects of GSK-3β inhibition and the interlinked molecular mechanisms still remain elusive. The present study explores whether high fat-high fructose diet (HFFD)-induced neuropathological changes could be alleviated by indirubin-3′-monoxime (IMX), a GSK-3β inhibitor. Male Swiss albino mice (8 weeks old) were fed with normal pellet or HFFD for 60 days. HFFD mice were treated with IMX once daily for last 7 days of the experimental period. HFFD fed-mice had significant amyloid deposits in cerebral cortex and hippocampus, and protein expression analyses showed activation of GSK-3β, nuclear translocation of NF-κB p65 and upregulation of inflammatory (TNF-α, IL-6, COX-2), astrocytic (GFAP), glial surface (CD-68) and pro-apoptotic markers (Bax and caspase-3). IMX treatment promotes the inhibitory phosphorylation of GSK-3β at Ser9 and moreover, a marked reduction in the phosphorylation of IKK-β, which prevents translocation and activation of NF-κB. Protein expression studies in IMX-treated brain tissues positively correlate with the anti-neuroinflammatory effects of GSK-3β inhibition. Taken together, our results provide substantial evidence that IMX could potentially attenuate neuroinflammation in coordination with the master transcription factor-NF-κB.Graphical abstractUnlabelled Image
       
  • Different doses of vitamin C supplementation enhances the Th1 immune
           response to early Plasmodium yoelii 17XL infection in BALB/c mice
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Xiaosong Qin, Jianhua Liu, Yunting Du, Ying Li, Li Zheng, Guang Chen, Yaming Cao Vitamin C (ascorbate) is maintained at high levels in most immune cells and can affect many aspects of the immune response. Here, we evaluated the effect of vitamin C supplementation on the immune response to Plasmodium yoelii 17XL (P. yoelii 17XL) infection in BALB/c mice. Two orally administered doses (25 mg/kg/day and 250 mg/kg/day) of vitamin C significantly reduced levels of parasitemia during the early stages of P. yoelii 17XL infection. The numbers of activated Th1 cells and macrophages in the groups receiving vitamin C supplementation were both higher than those in the untreated group. Meanwhile, vitamin C administration reduced the levels of tumor necrosis factor α secreted by splenocytes. Vitamin C also regulated the protective anti-malarial immune response by increasing the number of plasmacytoid dendritic cells, as well as the expression of dendritic cell maturation markers, such as major histocompatibility complex class II and cluster of differentiation 86. In conclusion, the doses of vitamin C (25 mg/kg/day, 250 mg/kg/day) during the early stages of malaria infection may better enhance host protective immunity, but have no dose dependence.
       
  • Dendritic cells treated by Trichinella spiralis muscle larval
           excretory/secretory products alleviate TNBS-induced colitis in mice
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Xuemin Jin, Yong Yang, Xue Bai, Haining Shi, Wenbao Zhang, Zhuangzhi Zhang, Wanzhong Jia, Jiaojiao Lin, Mingyuan Liu, Xiaolei Liu BackgroundTherapeutic potential of helminth have been shown to have a protective effect on immune-mediated diseases such as Crohn's disease (CD), which is associated with increased production of T helper cell type 1. However, helminth therapy is unacceptable to patients due to side-effects and the fear of parasites. As helminths regulate the cellular immune responses through innate cells such as dendritic cells (DCs), cellular immunotherapy has been considered a therapeutic option to treat CD.MethodsBone marrow-dendritic cells were generated, enriched and treated with Trichinella spiralis muscle larval excretory/secretory products (Ts-MLES). DCs maturation was measured by flow cytometry and cytokine production of DCs were measured by ELISA. Colitis was generated by intrarectal administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS) solution. For adoptive transfer, Ts-MLES treated-DCs injected intravenously 24 h prior to TNBS challenge. Disease activity index (DAI) including weight loss, diarrhea, and bloody stool were measured. Colon segments were stained with hematoxylin and eosin (H.E.) and periodic acid schiff (PAS) staining for histological damage scoring. The relative mRNA expression of cytokines in colon was analyzed by RT-PCR. Cytokine production in colon was measured by ELISA. Splenocytes were separated and cytokine profiles including Th1 (IFN-γ), Th2 (IL-4, IL-13), and Treg subsets (IL-10, TGF-β) were analyzed by flow cytometry.ResultsTs-MLES regulated the maturation and cytokine production of DCs. Ts-MLES -DC ameliorated the severity of the TNBS-induced colitis. In the colon and the spleen, Ts-MLES-DC decreased IFN-γ (Th1) significantly and increased Th2 (IL-4, IL-13)- and Treg (IL-10, TGF-β)- related cytokines.ConclusionsTs-MLES-DC ameliorated the severity of the TNBS-induced colitis through decreasing IFN-γ. Ts-MLES-DC skewed the Th1-mediated response toward the Th2 type and regulatory T cell response.
       
  • Circadian oscillation of TNF-α gene expression regulated by clock gene,
           BMAL1 and CLOCK1, in the Japanese medaka (Oryzias latipes)
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Teika Onoue, Goshi Nishi, Jun-ichi Hikima, Masahiro Sakai, Tomoya Kono To date, little information is available on the effects of circadian oscillation on immune regulation in lower vertebrates, such as teleost fish. In the present study, regulation of circadian oscillation of inflammatory cytokine TNF-α gene expression by clock gene was investigated using model fish medaka (Oryzias latipes). Firstly, structural analysis of clock genes was performed, which revealed that medaka BMAL1 and CLOCK1 conserve functionally important domains, such as basic helix-loop-helix (bHLH) and period-aryl hydrocarbon receptor nuclear translocator-single-minded (PAS), seen in their counterparts in other vertebrates. Expression of medaka Bmal1, Clock1, and Per1 genes was confirmed in central and peripheral tissues. Moreover, the expression of these clock genes and TNF-α genes in medaka acclimated to a 12:12 light (L) - dark (D) cycle showed circadian oscillation. In addition, higher expression of TNF-α gene was detected in medaka embryo cells (OLHdrR-e3) overexpressing Bmal1 and Clock1 genes. It was suggested that this increase was mediated by transcriptional regulation by clock proteins, which target E-box sequence in the cis-element of TNF-α gene as was detected by luciferase reporter gene assay. Moreover, in vitro head kidney stimulation with LPS at different zeitgeber time (ZT) under LD12:12 condition affected the degree of TNF-α gene expression, which shows high and low responsiveness to LPS stimulation at ZT18 and ZT10, respectively. These results suggested that fish TNF-α exhibited circadian oscillation regulated by clock proteins and its responsiveness against immune-stimulation depends on time zone.
       
  • Risk of infection with different immunosuppressive drugs combined with
           glucocorticoids for the treatment of idiopathic membranous nephropathy: A
           pairwise and network meta-analysis
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Defeng Liu, Yi Yang, Fu Kuang, Shuyun Qing, Bangqin Hu, Xian Yu IntroductionIdiopathic membranous nephropathy (IMN) is a common cause of nephrotic syndrome in adults and one of the leading causes of end-stage renal disease (ESRD). During recent years, the incidence of IMN has been increasing. The main treatment option for IMN is the use of immunosuppressive (IS) drugs combined with glucocorticoids (GC). However, the infection risk with different IS drug treatments has not been systematically compared. Therefore, a network meta-analysis was performed to compare the risk of infection of different IS drug treatments for IMN.MethodsRandomized controlled trials (RCTs) that assessed the risk of infection in patients with IMN treated with different IS drugs combined with GC were included in the network meta-analysis. Risk ratios for dichotomous data with 95% confidence intervals (CI) were calculated and the data were pooled with a random-effects model. The surface under the cumulative ranking area (SUCRA) was calculated to rank the risk of infection with different interventions.ResultsA total of 38 RCTs with 2066 participants were included for comparison of nine interventions. Tacrolimus combined with GC (TAC + GC) was associated with a significantly lower risk of infection than that with intravenous cyclophosphamide (IVCTX) + GC with a risk ratio (95% CI) of 0.52 (0.34–0.79). IVCTX + GC was associated with a significantly higher risk of infection than that with TAC + GC, cyclosporin (CSA) + GC, and oral cyclophosphamide (POCTX) + GC. A sensitivity analysis, excluding studies with a very long follow-up period, revealed minimal differences in the estimates. The SUCRA showed that CSA + GC had the lowest risk of infection (SUCRA 86.0%), and the second best treatment was POCTX + GC (SUCRA 78.6%). Conversely, IVCTX + GC (SUCRA 16.2%) had a higher risk of infection than that with the other IS drugs.ConclusionsCSA + GC and POCTX+ GC were associated with a lower risk of infection than that with other IS drugs combined with GC for IMN. Combined with comparative efficacy data, these results can help patients make informed decisions about treatment options for IMN.PROSPERO registration: CRD42018104849
       
  • Morin decreases cortical pyramidal neuron degeneration via inhibition of
           neuroinflammation in mouse model of schizophrenia
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Benneth Ben-Azu, Adegbuyi Oladele Aderibigbe, Abayomi Mayowa Ajayi, Aya-Ebi Okubo Eneni, Itivere Adrian Omogbiya, Olatunde Owoeye, Solomon Umukoro, Ezekiel O. Iwalewa Neuroinflammation plays a prominent role in the pathophysiology and progression of schizophrenia. Thus, suppression of neuroinflammation may retard the progression of the disease. This study was designed to investigate whether morin, a bioactive compound with antipsychotic-like activity could reduce biomarkers of neuroinflammation and neurodegeneration in lipopolysaccharide (LPS)- and ketamine (KET)-induced schizophrenic-like behavior in mice. Animals were treated once daily intraperitoneally with morin (100 mg/kg), haloperidol (1 mg/kg), risperidone (0.5 mg/kg), or saline (10 mL/kg) in combination with LPS (0.1 mg/kg) for 14 consecutive days. However, from days 8–14, overt schizophrenia-like episode was produced with i.p. injection of KET (20 mg/kg) once daily. Schizophrenic-like behaviors: positive (open-field test), negative (social-interaction and social-memory tests) and cognitive (Y-maze test) symptoms were assessed on day 14. Thereafter, the levels and expressions of biomarkers of neuroinflammation were estimated in the striatum (ST), prefrontal cortex (PFC) and hippocampus (HC) using spectrophotometry, ELISA and immunohistochemistry. The effects of morin on cortical pyramidal neurons were estimated using Golgi-impregnation staining technique. LPS in combination with KET significantly (p 
       
  • Doxycycline hyclate: A schistosomicidal agent in vitro with
           immunomodulatory potential on granulomatous inflammation in vivo
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Miriam Viviane Dias, Aline Pereira Castro, Camila Cabral Campos, Thaiany Goulart Souza-Silva, Reggiani Vilela Gonçalves, Raquel Lopes Martins Souza, Marcos José Marques, Rômulo Dias Novaes We investigated the effect in vitro and in vivo of doxycycline hyclate (Dx), a broad-spectrum antibiotic inhibitor of matrix metaloproteinases (MMPs), on adult Schistosoma mansoni worms and granulomatous liver inflammation in infected mice. Adult S. mansoni worms in culture treated with different concentrations of Dx (50–180 μg/mL) were studied for eight days to assess its morphology, eggs production, and mortality. Uninfected mice and those infected with S. mansoni, untreated and treated with praziquantel (Pz; 200 mg/kg) or Dx (50 mg/kg), were evaluated for 60 days. Our results indicated that Dx induced dose-dependent integumentary lesions (bubbles, tubercle collapse, spicule disappearance, peeling, and erosion), reduced mating rate and eggs-laying in adult S. mansoni worms. The effective lethal dose required to kill 50% of worms was 112.0 μg/mL Dx (DL50). In mice, S. mansoni infection induced hepatomegaly, intense IL-4, IL-10, TNF-α and TGF-β production, granulomatous inflammation and hepatic glycogen depletion. The number and size of the granulomas was similar in untreated and Dx-treated animals. Untreated animals showed a predominance of productive granulomas, and intense MMP-2 and MMP-9 activities. Dx-treated mice exhibited a significant increase in IL-4 levels, tissue inflammation, proportion of involutive granulomas, and hepatic collagenogenesis, as well as attenuated MMP-2 and MMP-9 activities. Our findings indicated that Dx is toxic to adult S. mansoni worms in vitro. However, in vitro beneficial effects were not reproduced in vivo, since Dx treatment increased liver granulomatous inflammation and collagenogenesis in S. mansoni-infected mice by a process potentially associated with Dx-mediated hepatic MMP-2 and MMP-9 inhibition.
       
  • Immunosuppressive effect of artemisinin and hydroxychloroquine combination
           therapy on IgA nephropathy via regulating the differentiation of CD4+ T
           cell subsets in rats
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Lixia Bai, Honglian Li, Jicheng Li, Jianping Song, Yuan Zhou, Bihao Liu, Ruirui Lu, Peichun Zhang, Junqi Chen, Dandan Chen, Yu Pang, Xusheng Liu, Junbiao Wu, Chunling Liang, Jiuyao Zhou Immunoglobulin A nephropathy (IgAN) is an autoimmune kidney disease with complex pathogenesis leading to end-stage renal damage. The crucial pathological characteristic in IgAN is IgA immune complexes deposition accompany with mesangial cell proliferation and mesangial matrix expansion. Artemisinin (ART) is isolated from traditional Chinese medicine Artemisia annua L. Hydroxychloroquine (HCQ) is a classical antimalarial drug used to treat autoimmune diseases. Both of them possess immunosuppressive, immunomodulatory and anti-inflammatory features. The aim of this study was to investigate the pharmacological effects of ART combined with HCQ (AH) and explore the underlying mechanisms in IgAN. In vivo, our results showed that AH could significantly improve kidney dysfunction, decrease mesangial matrix expansion as well as immune complexes in mesangial area visualized by H&E and PAS staining. The depositions of IgA immune complexes and complement 3 (C3) were obviously reduced after AH treatment by immunofluorescence. Interestingly, the morphology of kidney and spleen was significantly swelled but reverted by AH in IgAN rats. Further mechanistic study showed that the higher proportions of the Th2 and Th17 cells were reduced but the lower differentiation of Th1 and Treg cells subsets were promoted by AH. Taken together, this study demonstrated that there was an immunosuppressive effect of AH therapy on IgAN rats via regulating the differentiation of CD4+ T cell subsets, which provided an alternative approach for IgAN treatment.
       
  • Lupeol inhibits LPS-induced neuroinflammation in cerebellar cultures and
           induces neuroprotection associated to the modulation of astrocyte response
           and expression of neurotrophic and inflammatory factors
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Markley Silva Oliveira-Junior, Erica Patricia Pereira, Vanessa Cristina Meira de Amorim, Luã Tainã Costa Reis, Ravena Pereira do Nascimento, Victor Diogenes Amaral da Silva, Silvia Lima Costa In the central nervous system (CNS), neuroinflammation, especially that modulated by the cell response of astrocytes and microglia, is associated with damage to neurons in neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease and, Multiple Sclerosis. Lupeol is a dietary triterpene that has demonstrated biological activities as antioxidant. This study investigated the anti-inflammatory and neuroprotective effects of lupeol in an in vitro model of neuroinflammation in primary cerebellar cultures. Cultures were obtained from 6-day-old Wistar rats, subjected to inflammatory damage with lipopolysaccharide (LPS, 1 μg/mL) and treated with lupeol (0.1 μM). We observed, after a 48-hour treatment, through Fluorjade-B staining and immunocytochemistry (ICQ) for βIII-tubulin, that lupeol induced neuroprotection in cultures submitted to inflammatory damage. On the other hand, through ICQ for GFAP, it was possible to observe that lupeol modulated the astrocyte morphology for Bergmann glia-like phenotype and, especially for velate astrocyte-like phenotype, both phenotypes associated with the neuroprotective profile. Moreover, RT-qPCR analysis showed that lupeol induced the down-regulation of the mRNA expression for proinflammatory markers TNF, iNOS and NLRP3, as well as the production of nitric oxide (method of Greiss), which were up-regulated by LPS, and also induced up-regulation of the mRNA expression for arginase and IL-6 mRNA. In addition, lupeol induced up-regulation of mRNA expression for neurotrophins GDNF and NGF and also for the sonic hedgehog–Gli pathway. Together, these results lead to the conclusion that lupeol inhibits neuroinflammation in cerebellar cultures and induces neuroprotection associated with the modulation of astrocyte response and expression of neurotrophic and inflammatory factors.
       
  • CD24hiCD38hi B regulatory cells from patients with end plate inflammation
           presented reduced functional potency
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Chengping Xu, Meiyan Zhang, Kai Li, Ming Ni, Yunpeng Bai, Jun Zhang, Xin Song, Jian Wang Problem due to disc degeneration is frequently found in the aging population. However, severe pain and accompanying end plate inflammation is only found in a small subset of patients, who can be of a younger age than most people with severe disc degeneration, with no apparent cause. We hypothesized that deficiencies in B regulatory (Breg) cells might contribute to the aberrant inflammation in these patients. However, we found that the frequency of CD24hiCD38hi Breg cells was significantly higher in patients than in controls. To investigate Breg function, CD24hiCD38hi Breg cells were stimulated via CD40L/αIg and via Staphylococcus aureus Cowan. Interestingly, the expression of IL-10 and TGF-β1 was significantly lower in patients than in controls. The expression of PD-L1 was comparable between patient CD24hiCD38hi Bregs and control CD24hiCD38hi Bregs. Control CD24hiCD38hi Bregs, but not patient CD24hiCD38hi Bregs, could suppress the expression of TBX21 and RORC2 in stimulated CD4+ T cells, in a manner that was dependent on IL-10 and PD-L1. The expression of FOXP3, on the other hand, was dependent on TGF-β. In addition, PD-L1 reduced the viability of CD4+ T cells. Together, we demonstrated that the patients with end plate inflammation did not present a reduction in CD19+CD24hiCD38hi Breg frequency, but presented a reduction in CD19+CD24hiCD38hi Breg function.
       
  • The therapeutic potential of ginkgolide K in experimental autoimmune
           encephalomyelitis via peripheral immunomodulation
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Wen-Bo Yu, Qing Wang, Sheng Chen, Liang Cao, Jie Tang, Cun-Gen Ma, Wei Xiao, Bao-Guo Xiao Multiple sclerosis is a T cell-mediated inflammatory, demyelinating disease of the central nervous system, accompanied by neuronal degeneration. Based on the anti-inflammatory effects of Ginkgolide K (GK), a platelet activating factor antagonist, we explored the possible application of GK in the treatment of MS. The results showed that GK effectively ameliorated the severity of experimental autoimmune encephalomyelitis. The intervention of GK inhibited the infiltration of inflammatory cells and demyelination in the spinal cord. At the same time, the expression of the inflammation-related molecules TLR4, NF-κB, and COX2 in the spinal cord was significantly lower in the GK-treated mice, indicating that GK intervention can inhibit the inflammatory microenvironment of the spinal cord in EAE mice. In mouse spleen lymphocytes, GK increased the proportion of regulatory T cells (Treg) and reduced the proportion of T helper 17 cells (Th17), modifying the imbalance between Th17/Treg cells. Additionally, GK shifted macrophage/microglia polarization from M1 to M2 cell type. Importantly, GK inhibited the expression of chemotactic molecules CCL-2, CCL-3 and CCL-5, thereby limiting the migration of inflammatory cells to the spinal cord. Our results provide the possibility that GK may be a promising naturally small molecule compound for the future treatment of MS.
       
  • Taraxasterol suppresses inflammation in IL-1β-induced rheumatoid
           arthritis fibroblast-like synoviocytes and rheumatoid arthritis
           progression in mice
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Jianfeng Chen, Weibo Wu, Miaomiao Zhang, Caiming Chen Previous study has indicated that taraxasterol (TAR), one of bioactive pentacyclic triterpenes mainly isolated from Chinese medicine herb Taraxacum officinale, displays considerable anti-inflammatory effects in various kinds of models. However, its effects on rheumatoid arthritis (RA) have still not been elucidated. In this study, we aim to investigate its anti-inflammatory effects and underlying mechanisms of TAR against RA using both interleukin (IL)-1β-stimulated human fibroblast-like synoviocytes rheumatoid arthritis (HFLS-RA) in vitro and collagen-induced arthritis (CIA) mice in vivo. Firstly, our results demonstrated that TRA significantly suppressed the IL-1β-induced expressions of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), IL-6, and IL-8 and productions of matrix metalloproteinases (MMPs), like MMP-1 and MMP-3 in HFLS-RA in vitro. Moreover, TRA alleviated arthritis progressions and prevented inflammatory processes in the joint tissues of CIA mice in vivo. Further mechanism studies indicated that TRA blocked nuclear factor kappa B (NF-κB) activation via modulating inhibitor of kappa B (IκB), IκB kinase (IKK) and transforming growth factor-β-activated kinase 1 (TAK1). Results also demonstrated that TRA suppressed the NOD-like receptor protein 3 (NLRP3) inflammasomes through blocking expressions of NLRP3, apoptosis-associated speck-like protein containing (ASC), and caspase-1 in both IL-1β-induced HFLS-RA and CIA mice. In conclusions, current findings suggested that TRA might one of considerable therapeutic compounds for relieving rheumatoid arthritis progress via suppressing inflammations through modulating NF-κB and NLRP3 inflammasomes pathways.
       
  • TRPV2 suppresses Rac1 and RhoA activation and invasion in rheumatoid
           arthritis fibroblast-like synoviocytes
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Teresina Laragione, Carolyn Harris, Percio S. Gulko The TRPV2 cation channel has been recently implicated in the regulation of arthritis severity, joint damage, and in the invasive behavior of the fibroblast-like synoviocyte (FLS). However, its mechanism of action was unknown. In this study we characterize the cell signaling events mediating the TRPV2 suppressive activity in FLS invasiveness. Studies with FLS cell lines derived from patients with RA revealed that TRPV2-specific stimulation significantly reduced FLS adhesion to different extracellular matrices that shared binding to αν, β1 and β3 integrins. Localization of these integrins to the plasma membrane and numbers of thick and organized actin filaments were diminished by TRPV2 specific stimulation, and cells developed a round and non-polarized morphology. TRPV2 stimulation significantly reduced levels of activated RhoA, Rac1 and cofilin. RhoA activators were able to overcome the TRPV2-induced suppression on both RhoA activation and invasion. These new discoveries suggest that TRPV2 regulates key intracellular processes implicated in cell invasion in arthritis and other processes such as cancer, and has the potential to become a useful target for drug development.
       
  • Nonylphenol can aggravate allergic rhinitis in a murine model by
           regulating important Th cell subtypes and their associated cytokines
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Yun-xiu Wang, Zhao-wei Gu, Zhi-wei Cao, Li-ying Hao Nonylphenol (NP) is a widely distributed, toxic endocrine-disrupting chemical exhibiting estrogenic activity. However, its effect on allergic rhinitis (AR) remains unclear. In this study, the effects of NP on a murine model of AR were investigated. Mice were divided into ovalbumin (OVA), NP, and control groups. OVA was used for sensitization and challenge. Mice in the NP group were administered NP during the sensitization period. Allergic nasal symptoms and eosinophil counts in nasal mucosa were measured. Serum levels of OVA-specific IgE were determined by enzyme-linked immunosorbent assay. The mRNA levels of transcription factors of Th cells were determined with real-time polymerase chain reaction. Th cell subtypes and Treg numbers were counted with the aid of multi-color flow cytometry. Cytokine concentrations in nasal mucosa were determined using the cytometric bead array method. Subcutaneous injection of NP into mice exhibiting AR enhanced not only the nasal allergic symptoms, but also eosinophil infiltration and OVA-specific IgE. Moreover, NP upregulated IL-4, IL-5, IL-13, IL-9, IL-6 and IL-17, and downregulated IL-10, in the AR mouse model; IFN-γ and IL-23 were not affected. Transcription factors and Th cell percentages were evaluated to determine whether NP regulates Th cell subtypes in an AR mouse model. GATA3, PU.1, and RORγt levels were significantly increased, but FoxP3 and Helios were decreased. In addition, Th2, Th9, and Th17 subtype percentages significantly increased, and Treg cell percentages decreased, in NP administration groups; the percentage of Th1 subtypes was not affected. NP enhanced allergic inflammation in the AR mouse model through upregulation of Th2, Th9, and Th17 responses and negative regulation of Treg responses. These results suggest that NP may be trigger AR.
       
  • Elevated interleukin-35 suppresses liver inflammation by regulation of T
           helper 17 cells in acute hepatitis B virus infection
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Deng-Ke Teng, Yi Liu, Yi-Fei Lv, Li Wang, Wei Zhang, Jiu-Ping Wang, Yu Li Interleukin (IL)-35 is a responsive anti-inflammatory cytokine implicated in different diseases processes. It has been reported that elevated IL-35 contributed to immunosuppression in chronic hepatitis by modulation of T helper 17 (Th17) and regulatory T cells. However, the role of IL-35 in acute hepatitis B (AHB) was still not completely elucidated. Thus, in the present study, we analyzed the expression and regulatory activity of IL-35 to Th17 cells and inflammatory response during acute hepatitis B virus (HBV) infection in both peripheral blood cells isolated from AHB patients and in hydrodynamic induced HBV-infected mouse model. Plasma IL-35 level and circulating HBV peptides-induced Th17 frequency was significantly elevated in AHB patients, and IL-35 expression negatively correlated with liver inflammation. In vitro IL-35 stimulation to CD4+ T cells purified from AHB patients down-regulated HBV peptides-induced Th17-phenotype, which presented as reduced IL-17 and IL-22 production. In vivo IL-35 administration dampened liver inflammation in HBV plasmid injected mice, however, did not affect HBV antigens production. This process was accompanied by suppression of natural killer cells and down-regulation of HBV peptides-induced Th17 cells in the liver, but did not affect total intrahepatic lymphocytes and other cell subsets numbers or chemokines expression in the liver. In conclusion, the current data indicated that IL-35 might be a novel mediator associated with hepatocytes damage and liver inflammation by regulating HBV peptides-induced Th17 cells during acute HBV infection. The potential anti-inflammatory property of IL-35 might be pivotal for developing new therapeutic approaches for hepatitis B.
       
  • Application of highly efficient and lowly toxic bufadienolides screened
           from toad skin in lymphatic chemotherapy for colorectal cancer through a
           lymphatic metastatic model
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Changzheng He, Zhenyu Zou, Shaoyou Xia, Xiaowei Xing, Shidong Hu, Zilong Hu, Yuxuan Li, Songyan Li, Hongliang Zhang, Yu Yang, Yichen Liu, Xiaolei Xu, Boyan Liu, Yufeng Wang, Yingxin Xu, Xiaohui Du BackgroundLymph node metastasis (LNM) remains a major obstacle to treat colorectal cancer (CRC). Increasing evidences have suggested that bufadienolides contain several fractions displaying antitumor activity and may be applied in lymphatic chemotherapy. However, effects of the highly efficient and lowly toxic (HELT) bufadienolides on CRC in lymphatic chemotherapy have not been reported.MethodsAdenosine triphosphate tumor chemosensitivity assays (ATP-TCA) was performed to detect the inhibition rate (IR) of fractions of bufadienolides to cytokine-induced killer (CIK) cells and tumor cells. HELT fraction-loaded emulsions of different concentrations were prepared. Nude mouse bearing HCT116 tumors in footpad received high-dose emulsion (HD-E), middle-dose emulsion (MD-E), low-dose emulsion (LD-E), control emulsion (CE), Cinobufacini Injection (CI), or normal saline (NS), respectively. Hematoxylin and eosin (H&E) staining, Flow Cytometry (FCM), enzyme-linked immune sorbent assay (ELISA) and hematological examination were applied to evaluate therapeutic effects and potential toxicity.ResultsF18 and F19 were screened out as HELT fractions in vivo and F18-loaded emulsions of different concentrations for lymphatic administration were prepared. We confirmed that HD-E and MD-E produced obvious antitumor activities in footpad tumors and LNM compared with other groups in vitro. We also verified the effects of F18-loaded emulsions on activating hematopoietic function, stimulating proliferation of the spleen and natural killer (NK) cells, and promoting the secretion of IFN-γ and IgG1, although HD-E performed mild toxicity on liver.ConclusionThe present study demonstrated that lymphatic chemotherapy with HELT fraction of bufadienolides could be an effective approach to the treatment of CRC patients with LNM.
       
  • Peanut shell extract inhibits the development of dextran sulfate sodium
           (DSS)-induced colitis
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Ae Sin Lee, Kwang Min Lee, Jin-Ah Lee, InWook Choi Inflammatory bowel diseases (IBD) induce inflammation in the colon and small intestine. IBD include ulcerative colitis and Crohn's disease, with such common symptoms as severe diarrhea, fever, and blood in the stool. In the current study, we explored the ability of peanut shell extract (PSE) to alleviate IBD in an experimental colonic inflammation model. Colitis was induced by orally administered dextran sulfate sodium (DSS) in mice. Peanut shell extract was prepared using a method of aqueous ethanol. DSS treatment reduced the colon length and mouse body weight, and aggravated disease condition compared with untreated control mice. Oral administration of 400 mg/kg PSE alleviated colon shortening, body weight loss, DAI, and colon injury score in DSS-induced colitis. These physiological improvements were validated by reduced levels of proinflammatory cytokines and infiltrating macrophage accumulation in the inflamed colon in the PSE administered group. These observations suggest that PSE may be developed as an alternative natural extract for the prevention or treatment of IBD.
       
  • Thymulin treatment attenuates inflammatory pain by modulating spinal
           cellular and molecular signaling pathways
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Behzad Nasseri, Jalal Zaringhalam, Samira Daniali, Homa Manaheji, Zahra Abbasnejad, Vida Nazemian Thymulin is a peptide hormone which is mainly produced by thymic epithelial cells and it has immune-modulatory and anti-inflammatory effects. In this study, we investigated the effects of different doses and various timings of thymulin intraperitoneal administration on spinal microglial activity and intracellular pathways in an inflammatory rat model of Complete Freund's adjuvant (CFA). Thymulin treatment was implemented following CFA-induced inflammation for 21 days. After conducting behavioral tests (edema and hyperalgesia), the cellular and molecular aspects were examined to detect the thymulin effect on inflammatory factors and microglial activity. We demonstrated that thymulin treatment notably reduced thermal hyperalgesia and paw edema induced by CFA. Furthermore, molecular investigations showed that thymulin reduced CFA-induced activation of microglia cells, phosphorylation of p38 MAPK and the production of spinal pro-inflammatory cytokines (TNF-α, IL-6) during the study. Our results suggest that thymulin treatment attenuates CFA-induced inflammation. This effect may be mediated by inhibition of spinal microglia and production of central inflammatory mediators which seems to be associated with the ability of thymulin to reduce p38 MAPK phosphorylation. These data provide evidence of the anti-hyperalgesic effect of thymulin on inflammatory pain and characterize some of the underlying spinal mechanisms.
       
  • Dendritic cells modified with Der p1 antigen as a therapeutic potential
           for allergic rhinitis in a murine model via regulatory effects on IL-4,
           IL-10 and IL-13
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Shaoqing Yu, Ling Jin, Na Che, Ruxin Zhang, Feifei Xu, Bing Han ObjectivesHouse dust mites, including Der p1, are common allergens. The current study was designed to explore the allergen-specific immune tolerance effects of Der p1-modified dendritic cells (DCs) through IL-4, IL-10 and IL-13 on an allergic rhinitis (AR) mouse model.MethodsA lentivirus was modified to express Derp1. Then, immature DCs from mice were infected with this modified lentivirus to generate a lenti-Derp1-GFP DCs. 24 mice were random divided into four groups (n = 6 each), AR mouse were sensitized by Derp1 allergens and treated with lenti-GFP DCs (GFP-DC/AR group), or lenti-Derp1-GFP DCs (Der p1-DC/AR group) and dexamethasone (Dex/AR group), mice in the control group were treated with PBS instead of Der p1 then also intraperitoneally injected with 5 × 106 lenti-GFP DCs/mouse. AR symptoms expressed by each mouse were recorded. The proportions of CD4+CD25+Foxp3+ regulatory T cells among CD4+ T cells in the peripheral blood, and mRNA and protein expression levels of IL-4, IL-10, and IL-13 were measured.ResultsDCs infected with lenti-Derp1-GFP stimulated the maturation of DCs. Compared with the GFP-DC/AR group, mice in the Der p1-DC/AR group showed an ameliorated allergic response, a significant decrease in the levels of serum IgE, IgG1, and histamine, and a decrease in the expression of IL-4 and IL-13 mRNA and protein in the nasal mucosa. The expression of IL-10 increased in the Der p1-DC/AR group to a level similar to that observed in the Dex/AR group.ConclusionsThese results indicate that Der p1-modified DCs have therapeutic potential for AR via downregulation of IL-4 and IL-13, and upregulation of IL-10.
       
  • Prognostic value of IFN-γ, sCD163, CCL2 and CXCL10 involved in acute
           exacerbation of idiopathic pulmonary fibrosis
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Xianhua Gui, Xiaohua Qiu, Yaqiong Tian, Miaomiao Xie, Hui Li, Yujuan Gao, Yi Zhuang, Mengshu Cao, Hui Ding, Jingjing Ding, Yingwei Zhang, Hourong Cai ObjectiveAcute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is of concern because of its propensity for rapid deterioration and high mortality. Its aetiology and mechanism are still unclear. The aims of this study were to clarify the pathophysiology differences between AE-IPF and stable IPF (S-IPF) by comparing the serum levels of various cytokines and chemokines in the two groups and to identify those involvement in the occurrence of acute exacerbation and associated with mortality.MethodsThe study included 28 patients with AE-IPF, 32 patients with S-IPF, and 18 healthy control subjects. We measured the serum cytokine and chemokine levels in all cases by multiplex assay. Serum levels of cytokines and chemokines were compared between AE-IPF and S-IPF subjects. Logistic regression analysis was applied to identify the ability of these variables to predict acute exacerbation. Kaplan-Meier curves were used to analyse survival and Cox proportional hazard regression was used to identify predictors of survival.ResultsLevels of several cytokines and chemokines were significantly higher in both patient groups with IPF (with the exception of interleukin-2 [IL-2], chemokine cc-motif ligand 3, and RANTES [regulation upon activation normal T-cell express sequence]) than in healthy controls. Serum IL-1β (p = 0.008) and interferon (IFN)-γ (p = 0.007) levels tended to be higher in patients with AE-IPF than in those with S-IPF. The concentration of chemokine cc-motif ligand (CCL) 2 was significantly higher in bronchoalveolar lavage fluid than in serum (p = 0.001). Higher C-reactive protein, lactate dehydrogenase, percent forced vital capacity, percent diffusing capacity of the lung for carbon monoxide, and IFN-γ values in the patients with IPF were correlated with acute exacerbation status, with respective odds ratios of 1.241 (p = 0.011), 1.050 (p = 0.004), 1.043 (p = 0.001), 0.927 (p = 0.014), and 0.929 (p = 0.020). Acute exacerbation status was associated with an increased risk of mortality (hazard ratio 0.107, 95% confidence interval 0.036–0.314; p 
       
  • Matrine alleviates Staphylococcus aureus lipoteichoic acid-induced
           endometritis via suppression of TLR2-mediated NF-κB activation
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Kangfeng Jiang, Shuai Guo, Jing Yang, Junfeng Liu, Aftab Shaukat, Gan Zhao, Haichong Wu, Ganzhen Deng Endometritis is one of the main diseases that causes great economic losses in the dairy industry. Recent studies have shown that matrine extracted from the traditional Chinese herb Sophora flavescens is an alkaloid with a broad range of bioactivities. Here, we aimed to investigate the protective effects of matrine on Staphylococcus aureus lipoteichoic acid (LTA)-induced endometritis in mice and elucidate the possible molecular mechanisms in vitro. Histopathological changes showed that matrine remarkably attenuated the uterus injury in a mouse model of LTA-induced endometritis. qPCR and ELISA results showed that matrine dose-dependently reduced the expression of pro-inflammatory cytokines (TNF-α and IL-1β). To further elucidate the underlying mechanisms of this protective effect of matrine, LTA-stimulated bovine endometrial epithelial cells (bEECs) were employed in this study. The results demonstrated that TLR2 expression and its downstream nuclear factor (NF)-κB activation were both suppressed by matrine treatment. Furthermore, a small interference RNA targeting TLR2 gene mimicked matrine in its inhibition on LTA-induced activation of TLR2 and NF-κB. In conclusion, these findings suggest the protective effect of matrine against LTA-induced endometritis through negative regulation of TLR2-mediated NF-κB pathway.
       
  • Microglial LOX-1/MAPKs/NF-κB positive loop promotes the vicious cycle of
           neuroinflammation and neural injury
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Xin Ge, Dong-Mei Zhang, Meng-Meng Li, Yi Zhang, Xiang-Yang Zhu, Yong Zhou, Xiao Peng, Ai-Guo Shen Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), a member of the scavenger receptor family, recognizes multiple ligands and participates in several inflammatory responses, but its function within the central nervous system (CNS) remains unclear. In this study, we discovered an increased LOX-1 expression in activated microglia in vivo and in vitro. Employing the specific inhibitors, we found that conditioned medium of necrotic neurons (Necrotic-CM) induced microglial LOX-1 expression through the MAPKs/NF-κB pathway. Silencing LOX-1 inhibited MAPK phosphorylation, NF-κB-p65 nuclear transportation, and pro-inflammatory factor production in microglia exposed to Necrotic-CM. Furthermore, utilizing the conditioned medium of activated microglia (MG-CM), we discovered microglial LOX-1 aggravated the neuroinflammation-induced neuronal apoptosis. Collectively, a LOX-1/MPAKs/NF-κB positive loop might promote microglia activation and drive the vicious cycle of neuroinflammation and neuronal injury.
       
  • Protective effect of sophocarpine on lipopolysaccharide-induced acute lung
           injury in mice
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Ying Lu, Dan Xu, Jingyao Liu, Lina Gu Sophocarpine (SOP) is a tetracyclic quinolizidine alkaloid isolated from Sophora alopecuroides L. A number of studies have shown that SOP has anti-inflammatory actions and protects against a variety of tissue and organ injuries. The purpose of this study was to investigate the protective effects of SOP on LPS-induced acute lung injury (ALI) in mice. Lung histological alterations, edema, and MPO activity were measured in this study. Furthermore, the production of inflammatory cytokines and the expression of NF-κB and MAPKs signaling pathways were measured. The results showed that the LPS-induced lung histological alterations, edema, protein concentration, inflammatory cell level in BALF, MDA content, and MPO activity were significantly attenuated by SOP. The LPS-induced inflammatory cytokine TNF-α, IL-1β, and IL-6 were also inhibited by SOP. SOP also inhibited the LPS-induced IL-6 and IL-8 production in A549 cells. Western blot analysis demonstrated that SOP remarkably inhibited the phosphorylation of IκBα and NF-κB. LPS-induced MAPKs activation and TLR4 expression were also suppressed by treatment with SOP. In conclusion, the results indicate that SOP protects against LPS-induced ALI by inhibiting TLR4 signaling pathway.
       
  • Chikusetsusaponin V attenuates lipopolysaccharide-induced acute lung
           injury in mice by modulation of the NF-κB and LXRα
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Kai Su, Guangxin Zhang, Xu Zhang, Wei Jiang Acute lung injury (ALI) is an excessive and uncontrolled inflammatory response in lung, of which remains the leading cause of morbidity and mortality in worldwide. Chikusetsusaponin V (CsV), a bioactive compounds derived from Panacis Japonica, has been reported to have anti-inflammatory effects. However, it is still unclear whether CsV can protect mice against ALI. This study aimed to investigate the protective roles and potential mechanisms of CsV on lipopolysaccharide (LPS)-induced ALI in mice. The mice were pretreated with CsV (5, 10, and 20 mg/kg) four days before LPS treatment. 24 h later LPS administration, the histopathological changes, wet/dry ratio, and MPO activity in lung tissues were detected. The inflammatory cells, including total cells, neutrophils, and macrophages in the bronchoalveolar lavage fluid (BALF) were detected under a light microscope. The levels of pro-inflammatory cytokine TNF-α, IL-1β, and IL-6 in the BALF were assessed by ELISA. In addition, the expressions of NF-κB and LXRα in lung tissues were detected by western blot analysis. The results showed that pretreatment of CsV attenuated the lung histopathological damages, lung wet/dry ratio, and MPO activity induced by LPS. In addition, CsV also reduced the LPS-induced increases in the number of inflammatory cells and pro-inflammatory cytokine TNF-α, IL-1β, and IL-6 in the BALF. Furthermore, western blot analysis showed that CsV significantly inhibited the activation of NF-κB signaling pathway. CsV dose-dependently increased the expression of LXRα. In vitro, the anti-inflammatory effects of CsV can be reversed by LXRα inhibitor, GGPP. In conclusion, the results showed that CsV protected against LPS-induced ALI due to its ability to activate LXRα.
       
  • γδ T cells in hepatocellular carcinoma patients present cytotoxic
           activity but are reduced in potency due to IL-2 and IL-21 pathways
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Hang Jiang, Zhao Yang, Zhenyu Song, Mark Green, Haihan Song, Qinghua Shao Hepatocellular carcinoma (HCC) is the most common primary liver carcinoma and has one of the highest mortality rates of all cancers. The γδ T cells could infiltrate HCC and have demonstrated potent tumor-killing capacity. Here, we found that in peripheral blood, the vast majority of γδ T cells were Vδ2 T cells. In HCC patients, the frequency of Vδ2 T cells was significantly lower than in controls. γδ T cells that were harvested directly ex vivo possessed very limited capacity to eliminate Zol-loaded HCC cell lines, even at a high effector to target ratio. In vitro expansion with Zol could significantly increase the capacity of γδ T cells to eliminate HCC cell lines. But even with in vitro expansion, the γδ T cells from HCC patients presented significantly lower cytotoxic capacity than the γδ T cells from healthy individuals. The expression of IL-2 and IL-21 by γδ T cells was significantly lower in HCC patients than in control volunteers. Supplementing recombinant human IL-2 and IL-21 in the in vitro expansion culture increased the cytotoxic capacity of γδ T cells. In addition, the frequency of PD-1+ γδ T cells was significantly higher in HCC patients than in controls ex vivo, and was significantly elevated after in vitro expansion. Hep3B and HepG2 did not express PD-L1, while a small fraction of SNU-398 expressed PD-L1. Interestingly, co-incubation with γδ T cell elevated PD-L1 expression in HCC cell lines. Blocking PD-1 during in vitro expansion stage significantly elevated cytotoxicity toward all the HCC cell lines, while blocking PD-1 during the cytotoxicity assay significantly elevated cytotoxicity toward HepG2 and SNU-398, but not toward Hep3B. Overall, these results demonstrated that the circulating γδ T cells in HCC patients were reduced in cytotoxic capacity, possibly associated with the lack of IL-2 and IL-21 production and PD-1 upregulation.
       
  • Immunomodulatory properties of cimetidine: Its therapeutic potentials for
           treatment of immune-related diseases
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Abdollah Jafarzadeh, Maryam Nemati, Hossain Khorramdelazad, Zuhair Mohammad Hassan Histamine exerts potent modulatory impacts on the cells of innate- [including neutrophils, monocytes, macrophages, dendritic cells (DCs), natural killer (NK) cells and NKT cells] and adaptive immunity (such as Th1-, Th2-, Th17-, regulatory T-, CD8+ cytotoxic T cells, and B cells) through binding to histamine receptor 2 (H2R). Cimetidine, as an H2R antagonist, reverses the histamine-mediated immunosuppression, as it has powerful stimulatory effects on the effector functions of neutrophils, monocytes, macrophages, DCs, NK cells, NKT cells, Th1-, Th2-, Th17-, and CD8+ cytotoxic T cells. However, cimetidine reduces the regulatory/suppressor T cell-mediated immunosuppression. Experimentally, cimetidine potentiate some immunologic activities in vitro and in vivo. The therapeutic potentials of cimetidine as an immunomodulatory agent were also investigated in a number of human diseases (such as cancers, viral warts, allergic disorders, burn, and bone resorption) and vaccination. This review aimed to provide a concise summary regarding the impacts of cimetidine on the immune system and highlight the cellular mechanisms of action and the immunomodulatory effects of this drug in various diseases to give novel insights regarding the therapeutic potentials of this drug for treatment of immune-related disorders. The review encourages more investigations to consider the immunomodulatory characteristic of cimetidine for managing of immune-related disorders.
       
  • The selective NLRP3 inflammasome inhibitor MCC950 alleviates cholestatic
           liver injury and fibrosis in mice
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Junwen Qu, Zhiqing Yuan, Guiyang Wang, Xiaopeng Wang, Kewei Li Cholestasis occurs in many clinical circumstances and leads to severe liver disorders. MCC950, a small-molecule NLRP3 inhibitor, was previously shown to have anti-inflammatory effects. However, these effects have not yet been examined in cholestatic liver injury. This study aimed to investigate the role of NLRP3 inflammasome and test the therapeutic efficacy and molecular mechanisms of MCC950 in cholestatic liver injury through the common bile duct ligation (BDL) model in mice. The influence of MCC950 on histological changes, levels of liver damage, neutrophil infiltration, liver cell death, inflammatory cytokine levels, and NLRP3 inflammasome expression were examined. The results of the current study confirmed that NLRP3 components were up-regulated during bile duct obstruction. MCC950 treatment significantly alleviated BDL-induced liver injury by reducing production of the pro-inflammatory cytokines IL-1β and IL-18 and inhibiting neutrophil infiltration and hepatic cell death. Moreover, MCC950 significantly inhibited NLRP3 activation during cholestatic liver injury. In addition, transcriptome analysis indicated that Toll-like receptor signaling may be involved in the protective effects of MCC950 in cholestatic liver injury. In conclusion, experimental findings demonstrate that MCC950 exerted protective effects in cholestatic liver injury and liver fibrosis by blocking NLRP3 inflammasome activation and the mechanism was partially attributed to inhibition of Toll-like receptor signaling. The present study indicates MCC950 could potentially be an effective therapeutic strategy for the treatment of cholestatic liver injury.
       
  • MiR-128 mediates negative regulation in Staphylococcus aureus induced
           inflammation by targeting MyD88
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Xiaofei Ma, Shuai Guo, Kangfeng Jiang, Xiaoyan Wang, Nannan Yin, Yaping Yang, Arshad Zahoor, Ganzhen Deng Acute lung injury (ALI) is a common clinical syndrome of excessive uncontrolled inflammatory response in lung tissues with high mortality rates and limited therapeutic approaches. MicroRNAs (miRNAs) are a class of small non-coding RNAs which attach at 3′UTR of mRNA for further regulation of diverse proteins. MiRNAs are a current focus in regulating the inflammatory processes. The extent of pro-inflammatory gene activated against Staphylococcus aureus (S. aureus) is still unclear. Myeloid differentiation primary response 88 (MyD88) is involved in gram positive bacteria-induced lung inflammation by Toll-like receptors (TLRs). Then MyD88 activates NF-κB through IRAKs which are in charge of inflammation. Target prediction analyses revealed MyD88, a result of projections from multiple bio-websites, to be a putative target of miR-128. Here we probe the expression of the MyD88 and miRNA in mode of inflammation. We found up-regulated expression of MyD88 and down-regulation of miR-128 after S. aureus infection in mouse lung tissues and RAW264.7 cells via qPCR and western blotting (WB) analysis. Moreover, MyD88-miR-128 interaction was validated by luciferase assays. Then, we proved that miR-128 expression caused a reduction in IκBα and p65 phosphorylation and resulted in significant reduction in secretion of inflammatory cytokines, being consistent with the deletion of MyD88 in macrophages. It revealed that miR-128 specifically blocked the further development of inflammation through MyD88 down-regulation. Finally, we demonstrated a novel role of miR-128 that it mediates negative regulation in S. aureus induced inflammation by targeting MyD88.
       
  • Modification of IL-24 by tumor penetrating peptide iRGD enhanced its
           antitumor efficacy against non-small cell lung cancer
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Jie Yang, Jie Yang, Yanhong Wei, Hong Yin, Lin Fang, Dafei Chai, Huizhong Li, Hailong Li, Qing Zhang, Junnian Zheng Interleukin-24 (IL-24) is known for its tumor suppressive activity and the selective induction of apoptosis of numerous human cancer cells, while demonstrating little harm to normal cells. However, poor tumor penetration remains a key problem for the efficacy of IL-24 as a treatment. The iRGD (CRGDK/RGPDC) is a novel tumor-specific peptide with unique tumor-penetrating and cell-internalizing properties. To enhance the tumor-penetrating effects of IL-24, the iRGD peptide was fused with the C-terminal domain of IL-24 to generate a novel recombinant protein, IL-24-iRGD. The aim of the present study was to investigate the antitumor effects of IL-24-iRGD in non-small cell lung cancer (NSCLC) cells in vitro and in vivo. It was observed that IL-24-iRGD increased the production of IL-6, TNF-α and INF-γ from human peripheral blood monocyte (PBMC), and suppressed cell growth of A549 in vitro. Then A549 cells were subcutaneously injected into nude mice, and these tumor-bearing mice were immunized with IL-24, IL-24-iRGD or PBS via the tail vein. The IL-24 and IL-24-iRGD-treated groups exhibited tumor growth inhibition rates of 26.2% and 59.1%, respectively, when compared with the PBS-treated group. Protein penetration into tumors was analyzed by immunofluorescence, cell apoptosis was examined by TdT-mediated dUTP nick end labeling, and the expression of cleaved caspase-3 was analyzed by immuno-histochemical staining. The results demonstrated that IL-24-iRGD induced apoptosis and inhibited the growth of A549 cells to a significantly greater extent when compared with IL-24 treatment alone. It may provide an improved strategy for antitumor therapy and the clinical treatment of NSCLC.
       
  • Magnolol prevents ossified tendinopathy by inhibiting PGE2-induced
           osteogenic differentiation of TDSCs
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Wen Zhou, Xuemei Lin, Jun Chu, Tao Jiang, Huiyu Zhao, Bo Yan, Zhongmin Zhang Magnolol is a compound that is extracted from magnolia, is used in Chinese medicine and is a type of lignan. Magnolol has various anti-inflammation, anti-proliferation and pro-autophagy effects. Ossified tendinopathy affects many athletes and people with repetitive tendon injuries. Ossified tendinopathy is a tremendous economic burden, and no effective and safe drugs are available to prevent the pathogenesis of ectopic ossification. In this study, we aimed to study how magnolol affects ossified tendinopathy by evaluating its effects on osteogenic differentiation of tendon-derived stem cells (TDSCs). Our data suggested that magnolol attenuated ectopic ossification in the Achilles tendon caused by Achilles tenotomy. Magnolol inhibited PGE2-induced ALP activity and prevented calcium deposits in TDSCs in vitro. Magnolol also exerted inhibitory effects on expression of osteogenic factors, such as Runx2, OCN, and BMP2 in vivo. Further investigation revealed the underlying mechanism by which magnolol prevents PGE2-induced ectopic ossification. Specifically, magnolol inhibits PGE2-induced PI3K/AKT/β-catenin pathway activation in TDSCs. Our findings demonstrated that magnolol inhibited ossified tendinopathy through preventing osteogenic differentiation of TDSCs via downregulation PGE2-induced PI3K/AKT/β-catenin pathways.
       
  • Artemisinin enhances the anti-tumor immune response in 4T1 breast cancer
           cells in vitro and in vivo
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Yu Cao, Yong-Hui Feng, Li-Wei Gao, Xiao-Ying Li, Quan-Xiu Jin, Yu-Ying Wang, Ying-Ying Xu, Feng Jin, Shi-Long Lu, Min-Jie Wei BackgroundBreast cancer is a prominent cause of death among women worldwide. Recent studies have demonstrated that artemisinin (ART) displays anti-tumor activity. Using a mouse breast cancer model, we investigated the effects of ART in vitro and in vivo to determine how it influences the anti-tumor immune response.MethodsWe measured the proliferation and apoptosis of 4T1 cells in vitro after ART treatment by MTT assay and FACS. To examine the effects of ART in vivo, tumor volumes and survival rates were measured in 4T1 tumor-bearing mice. FACS was used to determine the frequencies of Tregs, MDSCs, CD4+ IFN-γ+ T cells, and CTLs in the tumors and spleens of the mice. mRNA levels of the transcription factors T-bet and FOXP3 and cytokines IFN-γ, TNF-α, TGF-β, and IL-10 were also determined by real-time RT-PCR. ELISA was used to measure TGF-β protein levels in the cell culture supernatants.ResultsART supplementation significantly increased 4T1 cell apoptosis and decreased TGF-β levels in vitro. ART also impeded tumor growth in 4T1 TB mice and extended their survival. MDSC and Treg frequencies significantly decreased in the 4T1 TB mice after ART treatment while CD4+ IFN-γ+ T cells and CTLs significantly increased. ART significantly increased T-bet, IFN-γ, and TNF-α mRNA levels within the tumor and significantly decreased TGF-β mRNA levels.ConclusionART supplementation hindered 4T1 tumor growth in vivo by promoting T cell activation and quelling immunosuppression from Tregs and MDSCs in the tumor.
       
  • Celastrol ameliorates Aspergillus fumigatus keratitis via
           inhibiting LOX-1
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Qiaoqiao Sun, Cui Li, Jing Lin, Xudong Peng, Qian Wang, Nan Jiang, Qiang Xu, Guiqiu Zhao PurposeTo investigate the effect of Celastrol (CLT) on Aspergillus fumigatus (A. fumigatus) keratitis.MethodsPrimary peritoneal macrophages of C57BL/6 mice were pretreated with CLT before A. fumigatus hyphae stimulation. C57BL/6 mice were infected with A. fumigatus. Mice corneas were treated with CLT from 1 day post infection. Clinical score, PCR, ELISA and Western blot were used to test expression of anti-inflammatory mediators, proinflammatory mediators and Lectin-like oxidized low-density lipoprotein receptor 1(LOX-1). The protein levels of p38MAPK after pretreated with CLT in macrophages of C57BL/6 mice challenged with A. fumigatus were tested by Western blot.ResultsC57BL/6 mice treated with CLT from 1 day post infection showed decreased disease, IL-1β, TNF-α, IL-10, TGF-β, MIP-2 and LOX-1 levels. CLT treatment markedly inhibiting mRNA and proteins levels of anti-inflammatory mediators, proinflammatory mediators and LOX-1 in macrophages of C57BL/6 mice compared with control group. CLT pretreatment before A. fumigatus stimulation obviously inhibiting protein levels of p38MAPK versus DMSO pretreated group in macrophages of C57BL/6 mice challenged with A. fumigatus.ConclusionThese data provide evidences that CLT ameliorates A. fumigatus keratitis of C57BL/6 mice via inhibiting LOX-1. CLT pretreatment before A. fumigatus stimulation decreased levels of inflammation in macrophages of C57BL/6 mice, which may be regulated by p-p38MAPK.
       
  • Beneficial effects of dual TORC1/2 inhibition on chronic experimental
           colitis
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Shurong Hu, Mengmeng Cheng, Rong Fan, Zhengting Wang, Lei Wang, Tianyu Zhang, Maochen Zhang, Edouard Louis, Jie Zhong Background and aimAZD8055, a new immunosuppressive reagent, a dual TORC1/2 inhibitor, had been used successfully in animal models for heart transplantation. The aim of this study was to evaluate the effects and mechanisms of AZD8055 on chronic intestinal inflammation.MethodsDextran sulfate sodium (DSS) - induced chronic colitis was used to investigate the effects of AZD8055 on the development of colitis. Colitis activity was monitored by body weight assessment, colon length, histology and cytokine profile analysis.ResultsAZD8055 treatment significantly alleviated the severity of colitis, as assessed by colonic length and colonic damage. In addition, AZD8055 treatment decreased the colonic CD4+ T cell numbers and reduced both Th1 and Th17 cell activation and cytokine production. The percentages of Treg cells in the colon were also expanded by AZD8055 treatment. Furthermore, AZD8055 effectively inhibited mTOR downstream proteins and signal transducer and activator of transcription related proteins in CD4+ T cells of intestinal lamina propria.ConclusionsThese findings increased our understanding of DSS-induced colitis and shed new lights on mechanisms of digestive tract chronic inflammation. Dual TORC1/2 inhibition showed potent anti-inflammatory and immune regulation effects by targeting critical signaling pathways. The results supported the strategy of using dual mTOR inhibitor to treat inflammatory bowel disease.
       
  • LRP1 receptor-mediated immunosuppression of α-MMC on monocytes
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Nianhua Deng, Minhui Li, Dai Shen, Qianchuan He, Wenkui Sun, Mengling Liu, Yang Liu, Yiping Zhou, Juecun Zheng, Fubing Shen Alpha-MMC is a type I ribosome-inactivating protein purified from bitter gourd that has strong anti-tumour and antiviral activity. Alpha-MMC also has immunosuppressive effects, but the mechanism of these immunosuppressive effects remains unclear. It is reported that the binding of α-MMC to its specific cell membrane LRP1 receptor is key to its biological effects. In this study, we investigated the effect of α-MMC on cytotoxicity and cytokine release regulation in three immune cells, human monocyte THP-1 cells, B-lymphocyte WIL2 cells and T-lymphocyte H9 cells, and explored the correlation between this effect and LRP1 receptor distribution on these three cell types. We demonstrate that α-MMC has a significant effect of apoptosis induction and cytokine release in THP-1 cells but has no effect on WIL2-S and H9 cells. Specifically, at a non-cytotoxic dose (80 μg/ml), α-MMC regulates THP-1 cells by inhibiting IL-1β, IL-2, IL-8, IL-9, IL-12, MIP-1α/β, MCP-1 and TNF-α expression and enhancing IL-1ra and RANTES expression, resulting in the inhibition of cellular immune function. Subsequent experiments showed that the cytokine expression regulated by α-MMC can be blocked by silencing the LRP1 receptor of α-MMC. Further research indicated that phosphorylation of 9 signalling proteins of the MAPK pathway was significantly regulated by α-MMC and was blocked by LRP1 silencing. We conclude that the regulation of cytokine expression induced by α-MMC in monocyte THP-1 cells is mediated by the LRP1 receptor, likely via the MAPK signalling pathway. Our results suggest that the inhibition effect on monocytes/macrophages mediates the immunosuppressive function of α-MMC. Due to the selective cytotoxicity and cytokine release regulation of α-MMC in monocytes/macrophages, α-MMC may be used for killing Tumour-Associated Macrophages (M2 subtypes) or inhibiting their cytokine release in the tumour microenvironment.
       
  • IMM-H004 protects against oxygen-glucose deprivation/reperfusion injury to
           BV2 microglia partly by modulating CKLF1 involved in microglia
           polarization
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Chen Chen, Qidi Ai, Shifeng Chu, Zhao Zhang, Xin Zhou, Piao Luo, Yingjiao Liu, Naihong Chen BackgroundIMM-H004 is a novel compound that has been shown to protect against cerebral ischemia/reperfusion injury in our previous works. Chemokine-like factor 1 (CKLF1) is a chemokine that exhibits increased expression in the ischemic brain. Dysregulation of microglia polarization dynamics is a mechanism of injury expansion poststroke.PurposesThe aim of present study was to investigate the effects of IMM-H004 on cell viability and microglia phenotypes in BV2 microglia suffering from oxygen-glucose deprivation/reperfusion and discussing the involvement of CKLF1 and possible mechanisms.ResultsIMM-H004 protected BV2 microglia from oxygen-glucose deprivation/reperfusion-induced toxicity. We found that the expression of CKLF1 was increased in BV2 microglia with oxygen-glucose deprivation/reperfusion, and IMM-H004 decreased this specially increased expression. Moreover, oxygen-glucose deprivation/reperfusion induced the BV2 microglia to polarize toward an M1 phenotype, and IMM-H004 modulated the polarization shift from the M1 phenotype and skewed toward the M2 phenotype, followed by suppressing the excessive inflammatory response and improving recovery. CKLF1 modulated BV2 microglia toward M1 polarization and induced an inflammatory response. By using receptor inhibitors, we found that OGD/R induced microglia polarization partly through CC chemokine receptor 4. Furthermore, the Co-IP assay showed that IMM-H004 decreased the amount of CKLF1 binding to CC chemokine receptor 4 in the BV2 microglia oxygen-glucose deprivation/reperfusion model.ConclusionsIMM-H004 protects BV2 microglia against oxygen-glucose deprivation/reperfusion injury partly by modulating microglia polarization and further regulating the inflammatory response. The CKLF1/CCR4 axis may be involved in the protective effects of IMM-H004 modulating microglia polarization.
       
  • Rituximab as an effective and probably safe treatment for granulomatosis
           with polyangiitis (Wegener's Granulomatosis)
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Soheil Tavakolpour, Samira Alesaeidi
       
  • Immunological modulation effects of an acid Epimedium polysaccharide on
           immune response in chickens
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Tao Qin, Zhe Ren, Lei Yi, Xiaopan Liu, Yang Luo, Yao Long, Song Peng, Jian Li, Yufang Ma, Yi Wu, Yifan Huang The purpose of the present study is to investigate the immunological activities of EPS-1 in the non-specific immune response and specific immune response of chickens. In vitro, the results showed that EPS-1 could increase the proliferation and cytokine secretion (IL-2, IL-4, IFN-γ and TNF-α) of spleen lymphocytes, expression of key surface molecules (MHC II, CD11c, CD40 and CD86) and cytokine secretion (TNF-α and IL-10) of matured chBM-DCs, phagocytic rate of matured chBM-DCs, and enhance the maturation and stimulating capacity of chBM-DCs. In vivo, EPS-1 could also prompt the HI antibody titer, boost the peripheral lymphocyte proliferation, enhance the release of cytokine products in blood (IFN-γ, IL-4 and IL-2) and duodenum (IL-17 and sIgA) of chickens. These results indicated that EPS-1 may have the potential as a powerful immune adjuvant in the treatment of chicken diseases.
       
  • Carvedilol attenuates experimentally induced silicosis in rats via
           modulation of P-AKT/mTOR/TGFβ1 signaling
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Manar Gamal Helal, Eman Said Silicosis is a well acknowledged occupational lung disorder with considerable negative impact on the patients' quality of life. Various signaling pathways have been reported to interplay in the pathogenesis of pulmonary fibro-proliferative disorders; of which, P-AKT/mTOR signaling pathway. The current study highlights the potential pulmonary protective effect of carvedilol; a non-selective α/β blocker against experimental silicosis-induced in rats by the intranasal installation of silica (50 mg/rat, 1 ml 0.9% NaCl). Carvedilol (20 mg/kg, orally) was administered for 8 weeks post intranasal silica installation. Carvedilol significantly attenuated silica-induced pulmonary damage on all the investigated scales. Inflammatory, oxidative/anti-oxidative and fibrotic incidences significantly improved with a significant histopathological restoration of lung architecture and attenuation of inflammatory and fibrotic biomarkers expression. Carvedilol significantly reduced lung contents of P-AKT and mTOR which, appears to be the main mechanism underlying the pulmonary protective effect of carvedilol. In conclusion; carvedilol attenuated silica-induced pulmonary fibrosis by modulating P-AKT/mTOR/TGFβ1 signaling and underlying inflammatory and fibrotic sequel.
       
  • Diosgenin ameliorates testicular damage in streptozotocin-diabetic rats
           through attenuation of apoptosis, oxidative stress, and inflammation
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Zeinab Khosravi, Reza Sedaghat, Tourandokht Baluchnejadmojarad, Mehrdad Roghani Diabetes mellitus (DM) is a prevalent metabolic disorder that is associated with development of some complications in male reproductive system including testicular damage, sexual dysfunction, abnormal spermatogenesis, and infertility. Diosgenin is a natural steroidal saponin with anti-diabetic, anti-oxidative, and anti-inflammatory effects. This research study was undertaken to explore the protective effect of diosgenin against diabetes-induced testicular damage in the rat. Ten days following streptozotocin (STZ; i.p.), diosgenin was daily administered for 6 weeks (p.o.). Diosgenin administration to diabetic rats significantly improved body weight and lowered serum glucose. In addition, diosgenin-treated diabetic group had a significantly lower level of malondialdehyde (MDA), protein carbonyl, greater level of glutathione (GSH), and higher activity of superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPx) in addition to testicular improvement of ferric reducing antioxidant power (FRAP). Furthermore, diosgenin significantly improved serum insulin and testosterone level and alleviated testicular markers of inflammation including tumor necrosis factor α (TNFα) and interleukin 6 (IL-6) in diabetic rats. Moreover, apoptotic markers including caspase 3 activity, Annexin V, and DNA fragmentation decreased, mitochondrial membrane potential (MMP) accentuated, and myeloperoxidase (MPO) activity as a biomarker of neutrophil infiltration decreased in diosgenin-treated diabetic group. Additionally, diosgenin was capable to improve sperm count, motility, and viability in addition to prevention of damage to seminiferous tubules in diabetic animals. Collectively, diosgenin ameliorates testicular damage in DM, at least via partial suppression of apoptosis, oxidative stress, inflammation, and neutrophil infiltration and also via partial restoration of mitochondrial integrity.
       
  • Polydatin alleviates traumatic spinal cord injury by reducing microglial
           inflammation via regulation of iNOS and NLRP3 inflammasome pathway
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Runxiao Lv, Lili Du, Xueyong Liu, Fenghua Zhou, Zhiqiang Zhang, Lixin Zhang Polydatin is a glucoside of resveratrol with lots of functional properties in the central nervous system, such as anti-edema, anti-oxidation and anti-inflammation. The purpose of this study was to evaluate the effects of polydatin on traumatic spinal cord injury (SCI) and explore the relative mechanisms. SCI models were established using the weight-drop method in rats, additionally, single polydatin administration (20, 40 mg/kg body weight) remarkably improved motor function of SCI rat, along with decreased nitric oxide (NO) generation and inflammatory factor (IL-1β, IL-6 and TNF-α) production in spinal cord tissues. Similar to the results of in vivo experiments, the inflammatory response was aggravated with the intervention of lipopolysaccharide (LPS) in BV2 microglia. However, polydatin treatment (1, 2 and 4 μM) inhibited iNOS expression, decreased NLRP3 inflammasome activation, which subsequently relieved microglial inflammation. Above all, our data indicated that polydatin possessed neuroprotective effects in SCI rats, possibly by suppressing iNOS expression and NLRP3 inflammasome activation in microglia.
       
  • Inhibitory effect of valproate sodium on pain behavior in diabetic mice
           involves suppression of spinal histone deacetylase 1 and inflammatory
           mediators
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Nehal M. Elsherbiny, Eman Ahmed, Ghada Abdel Kader, Yousra Abdel-mottaleb, Mohamed H. ElSayed, Amal M. Youssef, Sawsan A. Zaitone Anti-epileptic medications are included in the international guidelines for managing neuropathic pain. Valproate sodium (VPS) was recently described as “the forgotten analgesic” and has been reported to relief pain in various models of neuropathic pain. Some studies reported anti-inflammatory and histone deacetylase 1 (HDA1) inhibitory properties for sodium valproate. The aim of the current study was to investigate the modulatory effect of VPS on pain behavior and inflammatory reactions in alloxan-induced diabetic neuropathy focusing on HDA1 inhibition and glia reactivity. 28 Male Swiss albino mice were allocated into four groups, (1) vehicle group, (2) alloxan-diabetic group, (3 & 4) alloxan+VPS (25 or 50 mg/kg) groups. VPS was given daily for 5 weeks by oral gavage. Pain behavior demonstrated increased allodynia (von-Frey filaments) and hyperalgesia (hot-plate test) in alloxan-diabetic mice that was reduced significantly by at least one of VPS doses. Sciatic nerves in diabetic mice showed increased histopathology score, increased silver staining for the nerves-indicating myelopathy- and a decrease in immunostaining for nerve growth factor. Spinal cord of diabetic mice showed greater histopathologic score, increased CD11b and glia fibrillary acidic protein (GFAP) immunostaining than vehicle treated mice. Molecular investigations highlighted greater content of spinal histone deacetylases, tumor necrosis factor-α (TNF-α) and interlukin-1β (IL1β) that were favorably modified by VPS. Overall, the current data confirmed that the pain killing and anti-inflammatory activity of VPS is at least partly mediated through inhibition of spinal HDA1 and glia reactivity. These findings support the view of inviting antiepileptics for treating neuropathies.
       
  • Interleukin-33 prevents the development of autoimmune diabetes in NOD mice
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Jingli Lu, Yan Liang, Junjie Zhao, Haiyang Meng, Xiaojian Zhang IL-33/ST2 signal is important for the generation of forkhead box P3 (Foxp3)+ regulatory (Treg) cells, which contribute to immune homeostasis in the context of diseases. The aim of this study was to determine whether targeting IL-33/ST2 signal could establish immunological tolerance and prevent type 1 diabetes (T1D) in nonobese diabetic (NOD) mice. Female NOD mice treated with IL-33 for 4 weeks decreased the incidence and delayed the onset of autoimmune diabetes, whereas IL-33 did not revert blood glucose concentration and disease development in mice with new-onset diabetes. IL-33 reduced immune cell infiltration, increased the number of insulin-positive islet cells, as well as increased antiapoptosis molecule Bcl2 and reduced proapoptosis molecules Caspase3 at mRNA levels in the pancreas. IL-33 increased the expression of phosphorylated-Akt and phosphorylated-PI3K in the pancreas. Systemic administration of IL-33 increased the number of CD4+CD25+Foxp3+Treg cells and induced expression of Treg cell-associated molecules ST2 and GATA3 in splenic lymphocytes, and increased Foxp3, Ctla4, and Gata3 at the -mRNA level in pancreatic lymph nodes of NOD mice. IL-33 signaling stimulated activation of phosphorylation of p44/42 (Erk) and p38 MAPK, as well as CD39 in the spleen. Our results showed that IL-33 prevents disease development in prediabetic NOD mice, and highlight IL-33/ST2 as a potential therapeutic target to prevent T1D.
       
  • IL-21 reinvigorates exhausted natural killer cells in patients with
           HBV-associated hepatocellular carcinoma in STAT1-depedent pathway
    • Abstract: Publication date: May 2019Source: International Immunopharmacology, Volume 70Author(s): Yun Jin, Zhiwei Sun, Jiawei Geng, Lei Yang, Zhenyu Song, Haihan Song, Junfeng Wang, Jianzhong Tang Hepatocellular carcinoma (HCC) is the most common liver malignancy with dismal prognosis and limited treatment options. Natural killer (NK) cells are critical components of antitumor immunity due to their capacity to eliminate MHC class I-deficient cells. To evaluate the function of NK cells in HCC patients, circulating CD3−CD56+ NK cells were collected from HBV-associated HCC patients and healthy control individuals. Compared to NK cells from healthy controls, NK cells from HCC patients presented functional impairment, characterized by significantly reduced cytotoxicity, degranulation, and cytokine production. Exogenous IL-21 could reinvigorate NK cells from HCC patients, resulting in significantly increased levels of cytotoxicity, degranulation, and cytokine expression. However, IL-21-treated NK cells from HCC patients still presented lower response than IL-21-treated NK cells from healthy controls. IL-21 resulted in increased phosphorylation of both STAT1 and STAT3 in NK cells. Inhibition of STAT1, but not STAT3, significantly reduced IL-21-mediated reinvigoration of NK function. Together, this study demonstrated that NK cells in HBV-associated HCC patients presented functional impairments that could be reverted by IL-21 in a STAT1-mediated mechanism.
       
 
 
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