Selective inhibition of CDK7 ameliorates experimental arthritis in mice.

Abstract

Cyclin-dependent kinases (CDKs) have emerged as anti-inflammatory targets. The purpose of this study was to explore the therapeutic effects of a selective CDK7 inhibitor, BS-181, on mice with established collagen-induced arthritis (CIA). CIA mice were administered intraperitoneally with BS-181 (10mg/kg) twice daily for 2weeks. Control mice received vehicle only. Arthritis severity and joint histopathology were examined. The proinflammatory cytokines and anti-type II collagen antibodies (anti-CII) were determined by ELISA. IkB kinase (IKK)-β/NF-κB activation in the arthritic joints was assessed by Western blot. The ratio of Th17 cells was determined by flow cytometry. In vitro, splenocytes from mice with established CIA were stimulated with CII in the presence or absence of BS-181 and cytokines were detected. BS-181 treatment reduced the clinical score and histological damage in CIA mice. The serum proinflammatory cytokines (IL-6, IL-1β and IL-17) and anti-CII IgG2a levels were also decreased by BS-181 administration. Moreover, IKK-β/NF-κB signaling pathway was inhibited in arthritic joints. BS-181 administration also decreased the ratio of Th17 cells. In addition, CIA splenocytes pretreated with BS-181 produced less proinflammatory cytokines in vitro. These findings indicate that CDK7 inhibition by BS-181 is effective in the treatment of CIA, which might be mediated by suppression of IKK-β/NF-κB activation and Th17 cell response.