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Keywords:

  • Microglia;
  • Apoptosis;
  • Fas;
  • TGF-β;
  • FLIP

Abstract

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-α and IFN-γ, both being capable of sensitzing microglia to FasL, apoptosis of microglia is not a hallmark of inflammatory diseases of the CNS. In the present study, TGF-β is found to counteract the effect of TNF-α and IFN-γ to sensitize microglia to FasL-mediated apoptosis. Resistance to Fas-mediated apoptosis by TGF-β does not correlate with a down-regulation of Fas expression. As a key inhibitor of Fas-mediated apoptosis, we found expression of the cellular FLICE-inhibitory protein (c-FLIP) to be induced by TGF-β in resting as well as in activated microglia. Induction of FLIP was found to depend on a mitogen-activated protein kinase kinase (MKK)-dependent pathway as shown by the use of the specific MKK-inhibitor PD98059. The presence of FLIP strongly interfered with FasL-induced activation of caspase-8 and caspase-3 preventing subsequent cell death. The presented data provide the first evidence for a TGF-β-mediated FLIP in macrophage-like cells and suggest a mode of action for the anti-apoptotic role of TGF-β in the CNS.