Tumour necrosis factor-induced death of adult human oligodendrocytes is mediated by apoptosis inducing factor.
Tumour necrosis factor (TNF)-induced death of oligodendrocytes, the cell type targeted in multiple sclerosis, is mediated by TNF receptor p55 (TNFR-p55). The ligation of TNFR-p55 induces several signal transduction pathways; however, the precise mechanism involved in human oligodendrocyte (hOL) death is unknown. We defined that TNF-induced death of hOLs is non-caspase dependent, as evidenced by lack of generation of caspases 8, 1 and 3 active subunits; lack of cleavage of caspases 1 and 3 fluorogenic substrates; and lack of hOL death inhibition by the general caspase inhibitor, ZVAD.FMK. Electrophoresis of TNF-exposed hOL DNA revealed large-scale DNA fragmentation characteristic of apoptosis-inducing factor (AIF)-mediated cell death, and co-localization experiments showed that AIF translocation to the nucleus occurred upon exposure to TNF. AIF depletion by an antisense strategy prevented TNF-induced hOL death. These results indicate that TNF-induced death of hOLs is dependent on AIF, information of significance for the design strategies to protect hOLs during immune-mediated demyelination.
Jurewicz
Anna
A
Department of Neurology, Medical University of Lodz, Poland.
Matysiak
Mariola
M
Tybor
Krzysztof
K
Kilianek
Lukasz
L
Raine
Cedric S
CS
Selmaj
Krzysztof
K
D000328:Adult; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051033:Apoptosis Inducing Factor / Q000037:antagonists & inhibitors / Q000502:physiology*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002154:Calpain / Q000502:physiology; D020169:Caspases / Q000378:metabolism; D002403:Cathepsins / Q000502:physiology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D053938:DNA Fragmentation; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000502:physiology; D009836:Oligodendroglia / Q000187:drug effects* / Q000473:pathology; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D012697:Serine Endopeptidases / Q000502:physiology; D019311:Staurosporine / Q000494:pharmacology; D014178:Translocation, Genetic; D048069:Tumor Necrosis Factors / Q000494:pharmacology*
D051033:Apoptosis Inducing Factor; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; C506387:Cflar protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D048069:Tumor Necrosis Factors; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D002403:Cathepsins; D012697:Serine Endopeptidases; D002154:Calpain; D020169:Caspases; D019311:Staurosporine