Background Th17 cells, which are defined by a selective interleukin (IL)-17 secretion, are considered as a distinct lineage of CD4+ helper T cells which are regulated by the other Th1 and Th2 cytokines. IL-17A is a dominant proinflammatory cytokine produced by the Th17 cells. IL-21, IL-22 and IL-26 are also produced by the Th17 cells. In RA, IL-17A induces the production of proinflammatory mediators, such as IL-1 and tumor necrosis factor (TNF)-a from synovial fibroblasts, macrophages, and chondrocytes.
Objectives This study aimed to determine the regulatory effect of Th17 cytokines on the osteoclastogenesis in rheumatoid arthritis (RA).
Methods The expression of IL-17 and RANKL was determined in synovial tissue, fibroblast-like synoviocytes (FLS) and synovial fluids of RA patients using immonohistochemical staining, ELISA and real-time PCR. The Th17 cytokines-induced RANKL expression was studied in RA FLS using real-time PCR, luciferase activity, and western blot. Human peripheral blood monocytes were cultured with M-CSF and Th17 cytokines, and then osteoclastogenesis was determined by counting the number TRAP-positive multinucleated cells. The osteoclastogenesis was also determined after human monocytes were co-cultured with IL-17-prestimulated FLS.
Results There was significant correlation between RANKL and IL-17 levels in RA synovial fluid. After RA FLS were stimulated with IL-17, IL-21 and IL-22, the expression of RANKL mRNA increased and the IL-17-induced RANKL expression was decreased by the inhibition of Act1, TRAF6, NF-κB and the AP-1. Th17 cytokines and IL-17-prestimulated FLS induced osteoclastogenesis from monocytes in the absence of osteoblasts or RANKL.
Conclusions Th17 cytokines have a dual effect on osteooclastogenesis in RA; direct induction of osteoclastogenesis from monocytes and upregulation of RANKL production in RA FLS. Th17 cytokines/RANKL axis could be a potential therapeutic target for bone destruction in RA.
Disclosure of Interest None declared
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