Alamandine, a new member of the renin-angiotensin system (RAS), attenuates collagen-induced arthritis in mice via inhibiting cytokine secretion in synovial fibroblasts.

ABSTRACT

Alamandine is a novel component of the renin-angiotensin system (RAS) as well as an important biologically active peptide. It has predominantly been studied in cardiovascular context. However, its role in rheumatoid arthritis (RA) remains unknown. Here we illustrated its effects on inflammatory cytokines production by synovial fibroblasts from RA and pathological changes in collagen-induced arthritis (CIA) mice. Alamandine (0.1, 1 and 10 µg/ml) did not affect the survival of the synovial fibroblasts, but decreased the migration and proinflammatory cytokines expression in TNF-α (10 ng/ml) stimulated cells in vitro. Additionally, alamandine selectively decreased phosphorylated-JNK expression induced by TNF-a stimulation in RA FLS. DBA/1 J mice were induced arthritis by a primary injection with an emulsion of bovine type II collagen (CII) and complete Freund's adjuvant (day 0) and a booster injection of CII in incomplete Freund's adjuvant (day 21). Mice were then given alamandine intraperitoneally in saline (50 µg/kg/day) from days 21-42. Histology and multiplex immunobead assay showed that alamandine treatment inhibited the development of arthritis and reduced the joint damage. This effect was accompanied by the reduced inflammatory cytokines (IL-6, IL-23, IFN-γ) mRNA expression in local joints, the decreased TNF-α, IL-6, IL-17 and the increased IL-10 levels in the serum from alamandine administrated CIA mice. In conclusion, alamandine attenuates the development of arthritis by suppressing inflammatory cytokines expression in RA synovial fibroblasts via MAPK signaling pathway, suggesting a potential therapeutic role for RA.