Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adult
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Animals
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Apoptosis / drug effects
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Apoptosis Inducing Factor / antagonists & inhibitors
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Apoptosis Inducing Factor / physiology*
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CASP8 and FADD-Like Apoptosis Regulating Protein
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Calpain / physiology
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Caspases / metabolism
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Cathepsins / physiology
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Cell Death / drug effects
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Cell Death / physiology
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Cell Line
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DNA Fragmentation
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Humans
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Inhibitor of Apoptosis Proteins / metabolism
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Intracellular Signaling Peptides and Proteins / metabolism
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Membrane Potentials / drug effects
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Mice
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Mitochondrial Membranes / drug effects
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Mitochondrial Membranes / physiology
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Oligodendroglia / drug effects*
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Oligodendroglia / pathology
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Poly (ADP-Ribose) Polymerase-1
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Poly(ADP-ribose) Polymerases / metabolism
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Serine Endopeptidases / physiology
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Staurosporine / pharmacology
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Translocation, Genetic
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Tumor Necrosis Factors / pharmacology*
Substances
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Apoptosis Inducing Factor
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CASP8 and FADD-Like Apoptosis Regulating Protein
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CFLAR protein, human
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Cflar protein, mouse
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Inhibitor of Apoptosis Proteins
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Intracellular Signaling Peptides and Proteins
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Tumor Necrosis Factors
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PARP1 protein, human
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Poly (ADP-Ribose) Polymerase-1
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Poly(ADP-ribose) Polymerases
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Cathepsins
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Serine Endopeptidases
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Calpain
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Caspases
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Staurosporine