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  • Title: 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.
    Author: Spanaus KS, Schlapbach R, Fontana A.
    Journal: Eur J Immunol; 1998 Dec; 28(12):4398-408. PubMed ID: 9862377.
    Abstract:
    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 of APC and thereby limit reactivation of T cells that have invaded the CNS. In the present study we investigated the susceptibility of primary murine microglia and of the murine microglial cell line BV-2 to undergo Fas-mediated apoptosis. Whereas resting microglia are resistant to Fas ligand (FasL) treatment, induction of FasL-mediated apoptosis was achieved by treatment with 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 accompanied by increased amounts of mRNA for the apoptosis inhibitor FLIP, an effect which did not protect the cells from FasL-induced apoptosis. The FasL-induced cell death pathway in microglia involves reactive oxygen intermediates because the antioxidants N-acetylcysteine and glutathione interfere with induction of apoptosis. Surprisingly, microglia constitutively express FasL on the cell surface. However, blocking of endogenous Fas-FasL interaction with Fas-Fc fusion protein did not enhance the survival of microglia, excluding the possibility of suicide or fratricide mechanisms. By their expression of FasL and their TNF-alpha/IFN-gamma-dependent sensitivity to the pro-apoptotic effect of exogenous FasL, microglial cells may influence the course of T cell-mediated diseases of the CNS.
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