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 sensitizing microglia to FasL, apoptosis of microglia is not a hallmark of inflammatory diseases of the CNS. In the present study, TGF-beta is found to counteract the effect of TNF-alpha and IFN-gamma to sensitize microglia to FasL-mediated apoptosis. Resistance to Fas-mediated apoptosis by TGF-beta 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-beta 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-beta-mediated FLIP in macrophage-like cells and suggest a mode of action for the anti-apoptotic role of TGF-beta in the CNS.
Schlapbach
R
R
University Hospital Zurich, Department of Internal Medicine, Section for Clinical Immunology, Zurich, Switzerland.
Spanaus
K S
KS
Malipiero
U
U
Lens
S
S
Tasinato
A
A
Tschopp
J
J
Fontana
A
A
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D061945:Caspase Inhibitors; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D019014:fas Receptor / Q000502:physiology*
D061945:Caspase Inhibitors; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D016212:Transforming Growth Factor beta; D019014:fas Receptor; C505409:Casp3 protein, mouse; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9