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Cystathionine-γ-lyase ameliorates the histone demethylase JMJD3-mediated autoimmune response in rheumatoid arthritis

Cellular & Molecular Immunology volume 16, pages 694–705 (2019)Cite this article

Abstract

Cystathionine-γ-lyase (CSE), an enzyme associated with hydrogen sulfide (H2S) production, is an important endogenous regulator of inflammation. Jumonji domain-containing protein 3 (JMJD3) is implicated in the immune response and inflammation. Here, we investigated the potential contribution of JMJD3 to endogenous CSE-mediated inflammation in rheumatoid arthritis (RA). Upregulated CSE and JMJD3 were identified in synovial fibroblasts (SFs) from RA patients as well as in the joints of arthritic mice. Knocking down CSE augmented inflammation in IL-1β-induced SFs by increasing JMJD3 expression. In addition, CSE−/− mice with collagen-induced arthritis (CIA) developed severe joint inflammation and bone erosion. Conversely, overexpressing CSE inhibited JMJD3 expression by the transcription factor Sp-1 and was accompanied by reduced inflammation in IL-1β-treated SFs. Furthermore, JMJD3 silencing or the administration of the JMJD3 inhibitor GSK-J4 significantly decreased the inflammatory response in IL-1β-treated SFs, mainly by controlling the methylation status of H3K27me3 at the promoter of its target genes. GSK-J4 markedly attenuated the severity of arthritis in CIA mice. In conclusion, suppressing JMJD3 expression by the transcription factor Sp-1 is likely responsible for the ability of CSE to negatively modulate the inflammatory response and reduce the progression of RA.

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Acknowledgements

This work was supported by grants from National Natural Science Foundation of China (No. 81673428; 81330080), a key laboratory program of the Education Commission of Shanghai Municipality (No. ZDSYS14005).

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Authors and Affiliations

  1. Department of Pharmacology, Shanghai Key Laboratory of Bioactive Small Molecules, School of Pharmacy, Fudan University, Shanghai, 201203, China

    Weijun Wu, Ming Qin, Wanwan Jia, Di Yang, Mengwei Huang, Chenxi Xiao, Fen Long, Xinhua Liu & Yi Zhun Zhu

  2. State Key Laboratory of Quality Research in Chinese Medicine and School of Pharmacy, Macau University of Science and Technology, Macau, China

    Weijun Wu & Yi Zhun Zhu

  3. Institute of Arthritis Research, Shanghai Academy of Chinese Medical Sciences, Guanghua Integrative Medicine Hospital/Shanghai University of T.C.M, Shanghai, China

    Zheng Huang

  4. Ningbo The 9th Hospital, Ningbo, 315000, China

    Zhongzheng Li

  5. Department of Rheumatology, Shanghai Longhua Hospital, Shanghai, China

    Jianchun Mao

  6. Department of Pharmacology, National University of Singapore, Singapore, Singapore

    Philip K. Moore

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  1. Weijun Wu
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Wu, W., Qin, M., Jia, W. et al. Cystathionine-γ-lyase ameliorates the histone demethylase JMJD3-mediated autoimmune response in rheumatoid arthritis. Cell Mol Immunol 16, 694–705 (2019). https://doi.org/10.1038/s41423-018-0037-8

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