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

• Published in: Brain (London, England : 1878) England : 1878), 2005-11, Vol.128 (11), p.2675-2688
• Main Authors: Jurewicz, Anna, Matysiak, Mariola, Tybor, Krzysztof, Kilianek, Lukasz, Raine, Cedric S., Selmaj, Krzysztof
• Format: Article
• Language: English
• Subjects: Adult; AIF = apoptosis-inducing factor; Animals; anti-GFAP = anti-glial fibrillary acidic protein; anti-MBP = anti-myelin basic protein; Apoptosis - drug effects; apoptosis inducing factor; Apoptosis Inducing Factor - antagonists & inhibitors; Apoptosis Inducing Factor - physiology; asAIF = antisense AIF; Biological and medical sciences; Calpain - physiology; CASP8 and FADD-Like Apoptosis Regulating Protein; Caspases - metabolism; Cathepsins - physiology; cell death; Cell Death - drug effects; Cell Death - physiology; Cell Line; DNA Fragmentation; Drug toxicity and drugs side effects treatment; FACS = fluorescence-activated cell sorter; FADD = Fas-associated protein with death domain; hOL = human oligodendrocyte; Human viral diseases; Humans; Infectious diseases; Inhibitor of Apoptosis Proteins - metabolism; Intracellular Signaling Peptides and Proteins - metabolism; Medical sciences; Membrane Potentials - drug effects; Mice; Mitochondrial Membranes - drug effects; Mitochondrial Membranes - physiology; multiple sclerosis; Neurology; OL = oligodendrocyte; oligodendrocytes; Oligodendroglia - drug effects; Oligodendroglia - pathology; Pharmacology. Drug treatments; PI = propidium iodide; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases - metabolism; Serine Endopeptidases - physiology; Staurosporine - pharmacology; TNF = tumour necrosis factor; TNFR-p55 = TNF receptor p55; Toxicity: nervous system and muscle; TPCK = N-tosyl-l-phenylalanine chloromethyl ketone; TRADD = TNF-R1-associated death domain; Translocation, Genetic; Tumor Necrosis Factors - pharmacology; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids
• ISSN: 0006-8950; 1460-2156
• DOI: 10.1093/brain/awh627

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.