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.
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Disclosure of Interest None Declared
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