Role of GADD45β in the regulation of synovial fluid T cell apoptosis in rheumatoid arthritis

Rheumatoid arthritis (RA) is characterized by persistent Th1 cell infiltration and production of inflammatory cytokines in the location of joint lesion. It is known that infiltrated Th1 cells in the synovial fluid (SF) of RA patients are resistant to apoptosis. Here we demonstrate that Th1 cells accumulated in patient SF expressed a high level of GADD45 beta (Growth Arrest and DNA Damage-inducible 45 beta) which further inhibited Th1 cell apoptosis. Interestingly, in vitro culture of T cells with SF from RA patients increased GADD45 beta expression in Th1 cells and inhibited their apoptosis. Silencing of GADD45 beta by RNAi abolished the anti-apoptotic effect of RA SF, which was accompanied by down-regulation of Bcl-2 and up-regula tion of Bax. Further analysis showed that TNF-alpha and IL-12 in RA SF could stimulate GADD45 beta expression in Th1 cells and inhibit their apoptosis. Taken together, our results suggest a novel mechanism by which specific cytokines in the RA SF elevate GADD45 beta expression in local Th1 cells and subsequently leading to the enhanced T cell survival. (c) 2008 Elsevier Inc. All rights reserved.