Interleukin (IL)-25 suppresses IL-22 induced osteoclastogenesis in rheumatoid arthritis via STAT3 and p38 MAPK/IκBα pathway

Abstract

Background The present study aimed to evaluate the suppressive role of interleukin (IL)-25 in IL-22-induced osteoclastogenesis and receptor activator of nuclear factor κB ligand (RANKL) expression in rheumatoid arthritis (RA). Methods Serum from patients with RA and osteoarthritis (OA), and healthy controls, as well as synovial fluid from patients with RA and OA were collected, and the levels of IL-22 and IL-25 were measured. RA and OA synovial tissues were stained against IL-25. Fibroblast-like synoviocytes (FLSs) of patients with RA were cultured with IL-22, in the presence or absence of IL-25, and RANKL expression was measured by real-time PCR and enzyme-linked immunosorbent assay (ELISA). Human peripheral blood monocytes were cultured under IL-22/RANKL + M-CSF, with or without IL-25, and tartrate-resistant acid phosphatase (TRAP)-positive cells and osteoclast-related markers were investigated to determine osteoclastogenesis. Results Serum and synovial IL-25 levels in RA were up-regulated compared to those in OA and healthy control, and elevated expression of IL-25 in RA synovial tissue was re-confirmed. IL-25 and IL-22 levels showed significant correlation in serum and synovial fluid. Pre-treatment of FLS with IL-25 reduced IL-22-induced RANKL expression at the RNA level. The suppressive effects of IL-25 were confirmed to occur through the STAT3 and p38 MAPK/IκBα pathways. IL-25 reduced osteoclast differentiation and suppressed the expression of osteoclast-related markers. Conclusion In the current study, we demonstrated the regulatory effect of IL-25 on IL-22-induced osteoclastogenesis. Therapeutic approach involving augmentation of IL-25 regulatory response may serve as a novel treatment option for RA, especially by suppressing osteoclastogenesis.

Molecular and Cellular Heterogeneity in Rheumatoid Arthritis: Mechanisms and Clinical Implications

“…IL-2 is an important regulator of T cell-dependent responses and plays a crucial role in T cell proliferation and survival (132,162). The cytokine IL-22, produced by macrophages and Th22 cell subsets, is related to disease activity and promotes osteoclast production by inducing RANKL production in FLSs, while IL-25 produced by Th2 cells can inhibit this effect via the STAT3/P38/MAPK/IkBa pathway (163,164). In addition, IL-25 attenuates the development of CIA by inhibiting the differentiation of CD4+ T cells into Th17 cells (165,166).…”