Alternatively, Fas could contribute to synovial hyperplasia by inducing proliferation of Fas-expressing synovial fibroblasts and macrophages. tumor necrosis element (TNF-) and IL-6 were increased in the onset of disease. Since the contribution of synovial fibroblasts to swelling and joint damage is crucial, the potential activating effect of Fas on mouse fibroblast cell collection NIH3T3 was investigated. On treatment with anti-Fas in vitro, the cell death of NIH3T3 fibroblasts was reduced and the manifestation of proinflammatory cytokines TNF- and IL-6 was improved. These findings suggest that impairment of immune tolerance by increased T-cell reactivity does not lead to enhanced susceptibility to CIA and point to a role of Fas in joint destruction. Keywords: apoptosis, Fas, rheumatoid arthritis, tolerance Introduction Collagen-induced arthritis (CIA) is an animal model bearing Methylphenidate all the hallmarks of rheumatoid arthritis (RA). CIA can be induced in susceptible Rabbit Polyclonal to U12 strains of mice, e.g. DBA/1J, by immunization with bovine collagen type II in complete Freund’s adjuvant (CFA) [1]. CIA has been extensively studied to elucidate the pathological mechanisms relevant to human RA and to identify potential therapeutic targets [2]. The development of CIA, as of RA, is known to depend on T cells, and susceptibility to the disease is usually linked to the MHC region [3]. Following T-cell activation, an inflammatory cascade involving T cells, macrophages/monocytes, B cells, and activated synoviocytes is usually triggered. The different immune and local synovial cells produce a complex array of cytokines and other soluble mediators that are thought to be responsible for cartilage destruction and bone erosion [4-6]. One of the main features of CIA disease is usually synovial hyperplasia. The factors contributing to this phenomenon are unknown; however, an imbalance between rates of cell proliferation and cell death (apoptosis) has been suggested [7]. Two major pathways involved in ligand-mediated apoptosis in the immune system have been considered, namely the Fas ligand (FasL) and tumor necrosis factor (TNF) pathways. FasL and TNF are members of the TNF superfamily. Both cell-death pathways have been shown to contribute to peripheral tolerance and to the maintenance of homeostasis in the immune system through activation-induced cell death (AICD) [8-11]. Additionally, FasL together with perforin and TNF are the main pathways for killer cells, and mutations in those molecules block cytotoxicity of target cells [12,13]. Thus, cell-death pathways could contribute to the pathology of arthritis in at least two Methylphenidate ways: through promotion of autoimmunity by blocking tolerance of autoreactive lymphocytes and AICD, or through destruction of target tissues by induction of apoptosis or proliferation in susceptible cells. A pathogenic role of TNF- for arthritis is usually well documented in a number of studies and is supported by the success of anti-TNF therapy. Murine studies using TNF-receptor knockout mice and TNF transgenic mice point to a primary role in the local proliferation of synovial fibroblasts rather than to tolerance impairment of lymphocytes or death of local joint cells [14,15]. Although the exact role of Fas in arthritis remains unclear, some observations suggest an involvement of this receptor molecule in the disease process. It has been reported that a subset of T cells in patients with RA was resistant to Fas-mediated apoptosis [16,17]. Mysler and co-workers and other groups showed that Methylphenidate T cells in systemic Methylphenidate lupus erythematosus have an abnormal increase in surface Fas expression [18,19]. However, they showed proliferative and activating response to Fas crosslinking [20] rather than enhanced susceptibility to Fas-mediated Methylphenidate apoptosis. Several studies exhibited that autoreactive lymphocytes infiltrating the rheumatoid synovium are resistant to apoptosis either because of expression of the anti-apoptotic proteins bcl2 and bclxl or because of deficiency of FasL. Around the.