Interferon-gamma modulates human oligodendrocyte susceptibility to Fas-mediated apoptosis.
Interferon gamma (IFN-gamma) has been shown to be produced within multiple sclerosis (MS) lesions by infiltrating lymphocytes; systemic administration of this cytokine induces exacerbation of the disease. The aim of the current study was to establish the contribution of IFN-gamma to oligodendrocyte (OL) injury. Our studies utilized cultured human OLs, obtained by dissociation of surgically derived non-MS adult brain tissue. Neither cell survival nor myelin basic protein (MBP) gene expression were affected after 96 hours of treatment with IFN-gamma (100 U/ml), as assessed by LDH release, nucleosome enrichment assay, and RT-PCR. Expression of the death receptor Fas (CD95, APO-1) was, however, significantly increased. Furthermore, IFN-gamma-treated OLs became susceptible to Fas-mediated apoptosis when compared with untreated cells, and were protected by pretreatment with the caspase inhibitor ZVAD. TNF-alpha augmented the IFN-gamma-induced effect. Our results thus indicate that IFN-gamma is not directly cytotoxic for human OLs in culture, but could indirectly modulate functional injury-related responses by upregulating Fas on the cell surface.
Pouly
S
S
Montreal Neurological Institute, Neuroimmunology Unit, Quebec, Canada.
Becher
B
B
Blain
M
M
Antel
J P
JP
D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000943:Antigens, Differentiation / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D061945:Caspase Inhibitors; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004357:Drug Synergism; D005434:Flow Cytometry; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism* / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D004676:Myelin Basic Protein / Q000235:genetics / Q000378:metabolism; D009707:Nucleosomes / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D019014:fas Receptor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
D000911:Antibodies, Monoclonal; D000943:Antigens, Differentiation; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D004676:Myelin Basic Protein; D009707:Nucleosomes; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D007371:Interferon-gamma; D007770:L-Lactate Dehydrogenase