CD95 ligand (Fas-L/APO-1L) and tumor necrosis factor-related apoptosis-inducing ligand mediate ischemia-induced apoptosis in neurons.
Programmed cell death plays an important role in the neuronal degeneration after cerebral ischemia, but the underlying mechanisms are not fully understood. Here we examined, in vivo and in vitro, whether ischemia-induced neuronal death involves death-inducing ligand/receptor systems such as CD95 and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). After reversible middle cerebral artery occlusion in adult rats, both CD95 ligand and TRAIL were expressed in the apoptotic areas of the postischemic brain. Further recombinant CD95 ligand and TRAIL proteins induced apoptosis in primary neurons and neuron-like cells in vitro. The immunosuppressant FK506, which most effectively protects against ischemic neurodegeneration, prevented postischemic expression of these death-inducing ligands both in vivo and in vitro. FK506 also abolished phosphorylation, but not expression, of the c-Jun transcription factor involved in the transcriptional control of CD95 ligand. Most importantly, in lpr mice expressing dysfunctional CD95, reversible middle cerebral artery occlusion resulted in infarct volumes significantly smaller than those found in wild-type animals. These results suggest an involvement of CD95 ligand and TRAIL in the pathophysiology of postischemic neurodegeneration and offer alternative strategies for the treatment of cardiovascular brain disease.
Martin-Villalba
A
A
Department of Physiology, University of Heidelberg, D-69120 Heidelberg, Germany.
Herr
I
I
Jeremias
I
I
Hahne
M
M
Brandt
R
R
Vogel
J
J
Schenkel
J
J
Herdegen
T
T
Debatin
K M
KM
D000818:Animals; D017209:Apoptosis / Q000276:immunology / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D002478:Cells, Cultured; D053222:Fas Ligand Protein; D005260:Female; D020287:In Situ Nick-End Labeling; D002546:Ischemic Attack, Transient / Q000473:pathology / Q000503:physiopathology*; D008024:Ligands; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology* / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009474:Neurons / Q000276:immunology / Q000473:pathology / Q000502:physiology; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D053221:TNF-Related Apoptosis-Inducing Ligand; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*; D019014:fas Receptor / Q000276:immunology*
D051017:Apoptosis Regulatory Proteins; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; C505662:Faslg protein, rat; D008024:Ligands; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; C505655:Tnfsf10 protein, rat; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor