Pro-inflammatory Cytokines Elicit the Expression of Cell Cycle Regulator Cyclin-Dependent Kinase 6 in Rheumatoid Arthritis Synovial Fibroblasts

Abstract

Abnormal synovial proliferation is one of the major characteristics of rheumatoid arthritis (RA). However, the molecular mechanisms behind this process are still unclear. In this study, analysis of gene expression by quantitative real time-PCR was performed to identify cell cycle regulators whose expression is induced by pro-inflammatory cytokines in RA and osteoarthritis synovial fibroblasts. Stimulation with tumor necrosis factor (TNF) α or interleukin (IL) 1β, but not IL-6, induced gene expression of the cell cycle regulator, cyclin-dependent kinase (CDK) 6 in RA and osteoarthritis synovial fibroblasts. TNFα mediated CDK6 gene expression through both the NFκB and AP1 pathways. Furthermore, TNFα-stimulated proliferation of cultured RA synovial fibroblasts was inhibited by siRNA for CDK6 or CDK4, both of which are D-type cyclin partners. The expression of CDK6 is induced by TNFα through both the NFκB and AP1 pathways in RA synovial fibroblasts, suggesting that anti-CDK6 drugs might offer therapeutic benefits in RA.