The first two authors contributed equally to this work.
TGF-β induces the expression of the FLICE-inhibitory protein and inhibits Fas-mediated apoptosis of microglia
Article first published online: 30 NOV 2000
© 2000 WILEY-VCH Verlag GmbH, Weinheim, Fed. Rep. of Germany
European Journal of Immunology
Volume 30, Issue 12, pages 3680–3688, December 2000
How to Cite
Schlapbach, R., Spanaus, K.-S., Malipiero, U., Lens, S., Tasinato, A., Tschopp, J. and Fontana, A. (2000), TGF-β induces the expression of the FLICE-inhibitory protein and inhibits Fas-mediated apoptosis of microglia. Eur. J. Immunol., 30: 3680–3688. doi: 10.1002/1521-4141(200012)30:12<3680::AID-IMMU3680>3.0.CO;2-L
- Issue published online: 30 NOV 2000
- Article first published online: 30 NOV 2000
- Manuscript Accepted: 5 SEP 2000
- Manuscript Revised: 28 AUG 2000
- Manuscript Received: 30 MAR 2000
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.