TNF-alpha and IFN-gamma render microglia sensitive to Fas ligand-induced apoptosis by induction of Fas expression and down-regulation of Bcl-2 and Bcl-xL

The immune response in the central nervous system (CNS) involves microglial cells which represent intraparenchymal antigen-presenting cells (APC). To control immune effector mechanisms it may be required to induce apoptosis o f APC and thereby limit reactivation of T cells that have invaded the CNS. In the present study we investigated the susceptibility of primary murine m icroglia and of the murine microglial cell line BV-2 to undergo Fas-mediate d apoptosis. Whereas resting microglia are resistant to Fas ligand (Fast) t reatment, induction of Fast-mediated apoptosis was achieved by treatment wi th TNF-alpha or IFN-gamma. The effect of these cytokines was paralleled by up-regulation of Fas expression and down-regulation of Bcl-2 and Bcl-xL but not Bax. Activation of microglia by TNF-alpha and IFN-gamma was also accom panied by increased amounts of mRNA for the apoptosis inhibitor FLIP, an ef fect which did not protect the cells from Fast-induced apoptosis. The Fast- induced cell death pathway in microglia involves reactive oxygen intermedia tes because the antioxidants N-acetyl-cysteine and glutathione interfere wi th induction of apoptosis. Surprisingly, microglia constitutively express F ast on the cell surface. However, blocking of endogenous Fas-FasL interacti on with Fas-Fc fusion protein did not enhance the survival of microgtia, ex cluding the possibility of suicide or fratricide mechanisms. By their expre ssion of Fast and their TNF-alpha/IFN-gamma-dependent sensitivity to the pr o-apoptotic effect of exogenous Fast, microglial cells may influence the co urse of T cell-mediated diseases of the CNS.