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An apoptosis-independent role of TRAIL in suppressing joint inflammation and inhibiting T-cell activation in inflammatory arthritis

Cellular & Molecular Immunology volume 15, pages 846–857 (2018)Cite this article

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.

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Acknowledgements

We thank the core laboratory and Department of Medical Research of National Taiwan University Hospital for facility support. This work was supported by grants from the National Science Council, Taiwan (NSC 101-2321-B-002-008 and 104-2314-B-281-002-; MOST 105-2320-B-002-034- and 105-2320-B-038-065-).

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  1. These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Internal Medicine, Cathay General Hospital, Taipei, Taiwan, China

    I-Tsu Chyuan

  2. Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan, China

    I-Tsu Chyuan

  3. Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, China

    Hwei-Fang Tsai

  4. Department of Internal Medicine, Taipei Medical University Shuang Ho Hospital, Taipei, Taiwan, China

    Hwei-Fang Tsai

  5. Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan, China

    Hsiu-Jung Liao & Ping-Ning Hsu

  6. Division of Rheumatology, Department of Internal Medicine, Far Eastern Memorial Hospital, Taipei, Taiwan, China

    Chien-Sheng Wu

  7. Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan, China

    Ping-Ning Hsu

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  1. I-Tsu Chyuan
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Correspondence to Ping-Ning Hsu.

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Chyuan, IT., Tsai, HF., Liao, HJ. et al. An apoptosis-independent role of TRAIL in suppressing joint inflammation and inhibiting T-cell activation in inflammatory arthritis. Cell Mol Immunol 15, 846–857 (2018). https://doi.org/10.1038/cmi.2017.2

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