TGF-beta induces the expression of the FLICE-inhibitory protein and inhibits Fas-mediated apoptosis of microglia

During inflammatory reactions in the central nervous system (CNS), resident macrophages, the microglia, are exposed to Th1 cell-derived cytokines and pro-apoptotic Fas ligand (FasL). Despite the presence of TNF-alpha and IFN- gamma, both being capable of sensitzing microglia to FasL, apoptosis of mic roglia is not a hallmark of inflammatory diseases of the CNS. in the presen t study, TGF-beta is found to counteract the effect of TNF-alpha and IFN-ga mma to sensitize microglia to Fast-mediated apoptosis. Resistance to Fas-me diated apoptosis by TGF-beta does not correlate with a down-regulation of F as expression. As a key inhibitor of Pas-mediated apoptosis, we found expre ssion of the cellular FLICE-inhibitory protein (c-FLIP) to be induced by TG F-beta in resting as well as in activated microglia. induction of FLIP was found to depend on a mitogen-activated protein kinase kinase (MKK)-dependen t pathway as shown by the use of the specific MKK-inhibitor PD98059. The pr esence of FLIP strongly interfered with FasL-induced activation of caspase- 8 and caspase-3 preventing subsequent cell death. The presented data provid e the first evidence for a TGF-beta -mediated FLIP in macrophage-like cells and suggest a mode of action for the anti-apoptotic role of TGF-beta in th e CNS.