title: An apoptosis-independent role of TRAIL in suppressing joint inflammation and inhibiting T-cell activation in inflammatory arthritis.
abstract: Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has been implicated in the regulation of inflammation in rheumatoid arthritis (RA), primarily due to its ability to promote apoptosis in synoviocytes and infiltrating lymphocytes. The aim of this study was to investigate the immunomodulatory mechanism and role of TRAIL in inflammatory arthritis. We created an animal model of inflammatory arthritis and demonstrated that TRAIL significantly inhibited joint inflammation and reduced the severity of arthritis. The suppression of joint inflammation was not due to the TRAIL-mediated induction of apoptosis in T cells, macrophages or synovial fibroblasts. In contrast, TRAIL directly inhibited T-cell proliferation and suppressed the production of cytokines, which indicated that TRAIL exerted its anti-inflammatory effects by direct inhibition of T-cell activation. Moreover, TRAIL receptor (TRAIL-R)-knockout mice developed more severe disease, and the protective effects of TRAIL were abolished in the experimental arthritis model in TRAIL-R knockout mice. From these results, we conclude that TRAIL suppresses joint inflammation via an apoptosis-independent pathway and directly inhibits T-cell activation. Our results provide a novel apoptosis-independent, immune regulatory role for TRAIL in suppressing inflammatory arthritis and shed light on the development of effective new therapies for autoimmune inflammatory diseases.
authors.affiliation: Department of Internal Medicine, Cathay General Hospital, Taipei, Taiwan, China.|Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan, China.
authors.forename: I-Tsu
authors.initials: IT
authors.lastname: Chyuan
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, China.|Department of Internal Medicine, Taipei Medical University Shuang Ho Hospital, Taipei, Taiwan, China.
authors.forename: Hwei-Fang
authors.initials: HF
authors.lastname: Tsai
authors.affiliation: Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan, China.
authors.forename: Hsiu-Jung
authors.initials: HJ
authors.lastname: Liao
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Far Eastern Memorial Hospital, Taipei, Taiwan, China.
authors.forename: Chien-Sheng
authors.initials: CS
authors.lastname: Wu
authors.affiliation: Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan, China. phsu8635@ntu.edu.tw.|Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan, China. phsu8635@ntu.edu.tw.
authors.forename: Ping-Ning
authors.initials: PN
authors.lastname: Hsu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D049109:Cell Proliferation / Q000235:genetics; D005347:Fibroblasts / Q000276:immunology / Q000473:pathology; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051381:Rats; D017207:Rats, Sprague-Dawley; D013583:Synovial Membrane / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000276:immunology*
chemical_list: D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; C505655:Tnfsf10 protein, rat
keywords: T-cell activation; TRAIL; collagen-induced arthritis