Inhibition of glycogen synthase kinase-3β suppresses inflammatory responses in rheumatoid arthritis fibroblast-like synoviocytes and collagen-induced arthritis

Objectives: Glycogen synthase kinase (GSK)-3 beta, a serine/threonine protein kinase, has been implicated as a regulator of the inflammatory response. This study was performed to evaluate the effect of selective GSK-3 beta inhibitors in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) and collagen-induced arthritis (CIA). Method: FLS from RA patients were treated with selective GSK-3 beta inhibitors, including lithium chloride, 6-bromoindirubin-3'-oxime (BIO), or 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8). The effects of GSK-3 beta inhibition on pro-inflammatory mediators were determined by real-time PCR and ELISA. The levels of NF-kappa B, phosphorylated JNK, c-jun, ATF-2 and p-38 proteins were evaluated by western blot analysis. The in vivo effects of GSK-3 beta inhibitors were examined in mice with CIA. Results: Treatment of RA FLS with GSK-3 beta inhibitors induced dose-dependent reductions in gene expression and the production of pro-inflammatory mediators. The levels of NF-kappa B, phosphorylated JNK, c-jun, ATF-2 and p-38 were decreased following treatment with GSK-3 beta inhibitors. GSK-3 beta inhibitors treatment attenuated clinical and histological severities of CIA in mice. Infiltration of T-cells, macrophages, and tartrate-resistant acid phosphatase positive cells was decreased in joint sections of CIA mice by GSK-3 beta inhibitors treatment. Serum levels of IL-1 beta, IL-6, TNF-alpha. and IFN-gamma in CIA mice were also significantly decreased in dose-dependent manners by treatment with GSK-3 beta inhibitors. Conclusion: Treatment with GSK-3 beta inhibitors suppressed inflammatory responses in RA FLS and CIA mice. These findings suggest that the inhibition of GSK-3 beta can be used as an effective therapeutic agent for RA. (C) 2013 Societe francaise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.