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

Anna Jurewicz, Mariola Matysiak, Krzysztof Tybor, Lukasz Kilianek, Cedric S. Raine, Krzysztof Selmaj
2005 Brain  
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
more » ... genic 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 TNFinduced death of hOLs is dependent on AIF, information of significance for the design strategies to protect hOLs during immune-mediated demyelination. Abbreviations: AIF = apoptosis-inducing factor; anti-GFAP = anti-glial fibrillary acidic protein; anti-MBP = anti-myelin basic protein; asAIF = antisense AIF; FACS = fluorescence-activated cell sorter; FADD = Fas-associated protein with death domain; hOL = human oligodendrocyte; OL = oligodendrocyte; PI = propidium iodide; TNF = tumour necrosis factor; TNFR-p55 = TNF receptor p55; TPCK = N-tosyl-L-phenylalanine chloromethyl ketone; TRADD = TNF-R1-associated death domain
doi:10.1093/brain/awh627 pmid:16219674 fatcat:reielqz4rjbmnmtbb5s7cuucwa