FRI0050 CYR61 induces IL-6 production by fibroblast-like synoviocytes promoting TH17 differentiation in rheumatoid arthritis. (23rd January 2014)

• Record Type: Journal Article
• Authors: Li, N.L.; Lin, J.; Zhou, Z.; Huo, R.; Xiao, L.; Ouyang, G.; Li, N.
• Is Part Of: Annals of the rheumatic diseases. Volume 71(2012)Supplement 3
• Page Start: 326
• Page End: 326
• Publication Date: 2014-01-23
• Subjects: Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2012-eular.2507
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Background: Cyr61/CCN1 is a product of an immediate early gene which functions in mediating cell adhesion and inducing cell migration. We previously showed that increased production of Cyr61 by fibroblast-like synoviocytes (FLS) in RA promotes FLS proliferation and participates in RA pathogenesis with IL-17 dependent pathway. However, whether Cyr61 in turn regulates Th17 cell differentiation and further enhances inflammation of RA remained unknown. Objectives: To explored the potential role of Cyr61 as a pro-inflammatory factor to promote Th17 differentiation in RA pathogenesis. Methods: Th17 differentiation was studied in a co-culture system of CD4 + T and FLS cells. Collagen-induced arthritis (CIA) mice were used as the RA animal model to test the therapeutic effect of anti-Cyr61 antibody as well as its effect on IL-6 production by FLS and Th17 differentiation in vivo . Expression of cytokines was measured by ELISA, real-time PCR and flow cytometry, other factors by real-time PCR, western blotting or confocal microscopy. Results: Cyr61 stimulated IL-6 production by FLS, via the Cyr61/αvβ5/Akt/NF-kB signaling pathway. Increased IL-6 in turn promoted Th17 differentiation. Blocking Cyr61 action with a monoclonal antibody (093G9) reduced IL-6 production by FLS, attenuated Th17 response, and ameliorated disease progression in CIA mice. Conclusions: Cyr61 plays a critical role in stimulating IL-6 expression by FLS in RA and contributes to Th17 cell differentiation, and thus is likely a key molecule involved in the inflammation process of RA. Targeting Cyr61 may be a novel therapeutic strategy for RA. References: Firestein GS. Evolving concepts of rheumatoid arthritis. Nature 2003;423(6937):356-61. Gaffen SL. The role of interleukin-17 in the pathogenesis of rheumatoid arthritis. Curr Rheumatol Rep 2009;11(5):365-70. Zhang Q, Wu J, Cao Q, Xiao L, Wang L, He D, et al. A critical role of Cyr61 in interleukin-17-dependent proliferation of fibroblast-like synoviocytes in rheumatoid arthritis. Arthritis Rheum 2009;60(12):3602-12. Chen CC, Lau LF. Functions and mechanisms of action of CCN matricellular proteins. Int J Biochem Cell Biol 2009;41(4):771-83. Jun JI, Lau LF. Taking aim at the extracellular matrix: CCN proteins as emerging therapeutic targets. Nat Rev Drug Discovery 2011;10, doi: 10.1038/nrd3599 Zhou, L., Ivanov, II, R. Spolski, R. Min, K. Shenderov, T. Egawa, D. E. Levy, W. J. Leonard, and D. R. Littman. 2007. IL-6 programs T(H)-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol 8:967-974. Disclosure of Interest: None Declared