IL-37 Alleviates Rheumatoid Arthritis by Suppressing IL-17 and IL-17-Triggering Cytokine Production and Limiting Th17 Cell Proliferation.
IL-37, a new member of the IL-1 cytokine family, is a natural inhibitor of innate immunity associated with autoimmune diseases. This study was undertaken to evaluate whether IL-37 has antiarthritic effects in patients with rheumatoid arthritis (RA) and in mice with collagen-induced arthritis (CIA). In this study, we analyzed the expression of IL-37 in PBMCs, serum, and lymphocytes from RA patients as well as CD4(+) T cells polarized under Th1/Th2/Th17 conditions. The role of IL-37 was assessed by investigating the effects of recombinant human (rh)IL-37 and an adenovirus encoding human IL-37 (Ad-IL-37) on Th17 cells and Th17-related cytokines in RA patients and CIA mice. We found that active RA patients showed higher IL-37 levels compared with patients with inactive RA and healthy controls. Upregulated IL-37 expression also was found in CD3(+) T cells and CD4(+) T cells from RA patients and in Th1/Th17-differentiation conditions. rhIL-37 markedly decreased IL-17 expression and Th17 cell frequency in PBMCs and CD4(+) T cells from RA patients. Furthermore, IL-37 exerted a more suppressive effect on Th17 cell proliferation, whereas it had little or no effect on Th17 cell differentiation. IL-17 and IL-17-driving cytokine production were significantly reduced in synovium and joint cells from CIA mice receiving injections of Ad-IL-37. Our findings indicate that IL-37 plays a potent immunosuppressive role in the pathogenesis of human RA and CIA models via the downregulation of IL-17 and IL-17-triggering cytokine production and the curbing of Th17 cell proliferation.
Institute of Biological Therapy, Shenzhen University, Shenzhen 518060, China; Department of Pathogen Biology and Immunology, Shenzhen University School of Medicine, Shenzhen 518060, China; Shenzhen City Shenzhen University Immunodiagnostic Technology Platform, Shenzhen 518060, China;
Liang
L
Ye
Maoming City People's Hospital, Maoming 525000, Guangdong, China;
Bo
B
Jiang
Department of Pathology, University of Hong Kong, Hong Kong 999077, China;
Jun
J
Deng
Department of Laboratory Medicine, Peking University Shenzhen Hospital, Shenzhen 518036, China;
Jing
J
Du
Shenzhen Blood Center, Shenzhen 518035, Guangdong, China; and.
Wen
W
Xiong
Shenzhen University Diabetes Center, Shenzhen University Health Science Center, Shenzhen 518060, China.
Youfei
Y
Guan
Institute of Biological Therapy, Shenzhen University, Shenzhen 518060, China; Department of Pathogen Biology and Immunology, Shenzhen University School of Medicine, Shenzhen 518060, China; Shenzhen City Shenzhen University Immunodiagnostic Technology Platform, Shenzhen 518060, China;
Zhongyang
Z
Wen
Institute of Biological Therapy, Shenzhen University, Shenzhen 518060, China; Department of Pathogen Biology and Immunology, Shenzhen University School of Medicine, Shenzhen 518060, China; Shenzhen City Shenzhen University Immunodiagnostic Technology Platform, Shenzhen 518060, China;
Kunzhao
K
Huang
Institute of Biological Therapy, Shenzhen University, Shenzhen 518060, China; Department of Pathogen Biology and Immunology, Shenzhen University School of Medicine, Shenzhen 518060, China; Shenzhen City Shenzhen University Immunodiagnostic Technology Platform, Shenzhen 518060, China; zhuang809@126.com.
Zhong
Z
Huang
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000276:immunology*; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000276:immunology*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology*; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000276:immunology; D007375:Interleukin-1 / Q000097:blood / Q000276:immunology* / Q000627:therapeutic use; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology; D051379:Mice; D008811:Mice, Inbred DBA; D012333:RNA, Messenger / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D013583:Synovial Membrane / Q000166:cytology / Q000276:immunology / Q000473:pathology; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology
D000893:Anti-Inflammatory Agents; C508587:IL37 protein, human; D007375:Interleukin-1; D020381:Interleukin-17; D012333:RNA, Messenger; D011994:Recombinant Proteins