title: GITRL modulates the activities of p38 MAPK and STAT3 to promote Th17 cell differentiation in autoimmune arthritis.
abstract: The glucocorticoid-induced TNFR family-related protein (GITR) and its ligand play a critical role in the pathogenesis of autoimmune arthritis by enhancing the Th17 cell response, but their molecular mechanisms remain largely unclear. This study aims to define the role of p38 mitogen-activated protein kinases (MAPK) and signal transducer and activator of transcription 3 (STAT3) signaling in GITRL-induced Th17 cells in autoimmune arthritis. We found that the p38 phosphorylation was enhanced by GITRL in activated CD4+T cells, and the p38 inhibitor restrained the GITRL-induced Th17 cell expansion in a dose-dependent manner. Moreover, there was decreased STAT3 activity on Tyr705 and Ser727 with the p38 inhibitor in vitro. Notably, the p38 inhibitor could prevent GITRL-treated arthritis progression and markedly decrease the Th17 cell percentages. The phosphorylation of the Tyr705 site was significantly lower in the GITRL-treated CIA mice administrated with the p38 inhibitor. A significantly higher phosphorylation of p38 was detected in RA patients and had a positive relationship with the serum level of anti-cyclic citrullinated peptide (anti-CCP) antibody. Our findings have indicated that GITRL could promote Th17 cell differentiation by p38 MAPK and STAT3 signaling in autoimmune arthritis.
authors.affiliation: Department of Laboratory Medicine, The Affiliated People's Hospital, Jiangsu University, Zhenjiang, China.
authors.forename: Xinyi
authors.initials: X
authors.lastname: Tang
authors.affiliation: Institute of Laboratory Medicine, Jiangsu Key Laboratory of Laboratory Medicine, Jiangsu University, Zhenjiang, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Tian
authors.affiliation: Institute of Laboratory Medicine, Jiangsu Key Laboratory of Laboratory Medicine, Jiangsu University, Zhenjiang, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Ma
authors.affiliation: Institute of Laboratory Medicine, Jiangsu Key Laboratory of Laboratory Medicine, Jiangsu University, Zhenjiang, China.
authors.forename: Jiemin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Institute of Laboratory Medicine, Jiangsu Key Laboratory of Laboratory Medicine, Jiangsu University, Zhenjiang, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Qi
authors.affiliation: Institute of Laboratory Medicine, Jiangsu Key Laboratory of Laboratory Medicine, Jiangsu University, Zhenjiang, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Rui
authors.affiliation: Institute of Laboratory Medicine, Jiangsu Key Laboratory of Laboratory Medicine, Jiangsu University, Zhenjiang, China.
authors.forename: Yungang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Institute of Laboratory Medicine, Jiangsu Key Laboratory of Laboratory Medicine, Jiangsu University, Zhenjiang, China.
authors.forename: Huaxi
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong, China.
authors.forename: Liwei
authors.initials: L
authors.lastname: Lu
authors.affiliation: Department of Laboratory Medicine, The Affiliated People's Hospital, Jiangsu University, Zhenjiang, China.|Institute of Laboratory Medicine, Jiangsu Key Laboratory of Laboratory Medicine, Jiangsu University, Zhenjiang, China.
authors.forename: Shengjun
authors.initials: S
authors.lastname: Wang
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001168:Arthritis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D001327:Autoimmune Diseases / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016022:Case-Control Studies; D002454:Cell Differentiation; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D008875:Middle Aged; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C478967:TNFSF18 protein, human; D048069:Tumor Necrosis Factors; D048051:p38 Mitogen-Activated Protein Kinases
keywords: GITRL; Immune response; Immunity; Immunology and Microbiology Section; STAT3; Th17 cells; autoimmune arthritis; p38 MAPK