Tumour necrosis factor-induced death of adult human oligodendrocytes is mediated by apoptosis inducing factor.

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.

• Authors: Anna Jurewicz, Mariola Matysiak, Krzysztof Tybor, Lukasz Kilianek, Cedric S Raine, Krzysztof Selmaj
• Journal: Brain : a journal of neurology (Brain) Vol. 128 Issue Pt 11 Pg. 2675-88 (Nov 2005) ISSN: 1460-2156 [Electronic] England
• PMID: 16219674 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Apoptosis Inducing Factor
• CASP8 and FADD-Like Apoptosis Regulating Protein
• CFLAR protein, human
• Cflar protein, mouse
• Inhibitor of Apoptosis Proteins
• Intracellular Signaling Peptides and Proteins
• Tumor Necrosis Factors
• PARP1 protein, human
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerases
• Cathepsins
• Serine Endopeptidases
• Calpain
• Caspases
• Staurosporine

Topics

• Adult
• Animals
• Apoptosis (drug effects)
• Apoptosis Inducing Factor (antagonists & inhibitors, physiology)
• CASP8 and FADD-Like Apoptosis Regulating Protein
• Calpain (physiology)
• Caspases (metabolism)
• Cathepsins (physiology)
• Cell Death (drug effects, physiology)
• Cell Line
• DNA Fragmentation
• Humans
• Inhibitor of Apoptosis Proteins (metabolism)
• Intracellular Signaling Peptides and Proteins (metabolism)
• Membrane Potentials (drug effects)
• Mice
• Mitochondrial Membranes (drug effects, physiology)
• Oligodendroglia (drug effects, pathology)
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerases (metabolism)
• Serine Endopeptidases (physiology)
• Staurosporine (pharmacology)
• Translocation, Genetic
• Tumor Necrosis Factors (pharmacology)