MODULATION BY PROINFLAMMATORY CYTOKINES OF FAS FAS LIGAND-MEDIATED APOPTOTIC CELL-DEATH OF SYNOVIAL-CELLS IN PATIENTS WITH RHEUMATOID-ARTHRITIS (RA)/

Synovial cell hyperplasia is a characteristic of patients with RA, Exc essive proliferation of RA synovial calls is, in part, responsible for the synovial cell hyperplasia. In addition, synovial cell death that would reduce synovial cell number may be defective, leading to the hyp erplasia. Thus, the defective control of cell death as well as cell pr oliferation may be of central importance in the pathogenesis of RA. In this study we analysed effects of proinflammatory cytokines on Fas/Fa s ligand (FasL)-induced synovial cell apoptosis, and evaluated apoptos is-associated protein expression in the synovial cells in patients wit h RA. RA synovial cells expressed Fas antigen and lymphocytes infiltra ting into RA synovium expressed Fast. Apoptotic synovial cells were de tected within the sublining layer of RA synovium. Anti-Fas MoAb induce d apoptosis of RA synovial cells in vitro, and proinflammatory cytokin es tumour necrosis factor-alpha (TNF-alpha) and IL-1 beta, but not IL- 6 or IL-8, inhibited the anti-Fas-induced apoptosis accompanying up-re gulation of Bcl-2 protein expression and reduced expression of CPP32 a nd ICH 1L. Immunohistochemical study revealed that CPP32 and ICH-1L we re expressed weakly in the RA synovial lining cells compared with oste oarthritis (OA) synovial lining cells. Thus, we found that although RA synovial cells could die via apoptosis through Fas/FasL pathway, apop tosis of synovial cells was inhibited by proinflammatory cytokines pre sent within the synovium. Inhibition of apoptosis by the proinflammato ry cytokines may contribute outgrowth of synovial cells that leads to pannus formation and the destruction of joints in patients with RA.