title: Involvement of de novo ceramide biosynthesis in lymphotoxin-induced oligodendrocyte death.
abstract: Both experimental and clinical studies suggest that lymphotoxin (LT) plays an important role in multiple sclerosis (MS) by inducing oligodendrocyte (OL) depletion. However, the mechanism of LT cytotoxicity is unknown. Because of the role of ceramide as a cell death mediator for a large variety of cytotoxic molecules, we have investigated the possible role of this second messenger in LT-induced cytotoxicity on SV40 immortalized new-born mice OL. Human recombinant LT exposure (50 ng/ml) resulted in intracellular ceramide accumulation which peaked at 48 h (approximately 170% increase) and paralleled LT-induced cytotoxicity. Moreover, fumonisin B1, a potent and specific ceramide synthase inhibitor, not only inhibited ceramide accumulation but also protected OL from LT cytotoxicity. These results suggest that LT-induced ceramide synthase stimulation and subsequent increased intracellular ceramide concentration are implicated in oligodendrocyte death.
authors.affiliation: INSERM E 9910, Institut Claudius Régaud, Toulouse, France.
authors.forename: I
authors.initials: I
authors.lastname: Plo
authors.forename: S
authors.initials: S
authors.lastname: Ghandour
authors.forename: A C
authors.initials: AC
authors.lastname: Feutz
authors.forename: M
authors.initials: M
authors.lastname: Clanet
authors.forename: G
authors.initials: G
authors.lastname: Laurent
authors.forename: A
authors.initials: A
authors.lastname: Bettaieb
mesh_terms: D000818:Animals; D002264:Carboxylic Acids / Q000494:pharmacology; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects; D002518:Ceramides / Q000096:biosynthesis*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D037341:Fumonisins; D006801:Humans; D008233:Lymphotoxin-alpha / Q000494:pharmacology*; D051379:Mice; D009836:Oligodendroglia / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D011994:Recombinant Proteins / Q000494:pharmacology
chemical_list: D002264:Carboxylic Acids; D002518:Ceramides; D004791:Enzyme Inhibitors; D037341:Fumonisins; D008233:Lymphotoxin-alpha; D011994:Recombinant Proteins; C056933:fumonisin B1; D010088:Oxidoreductases; C108138:dihydroceramide desaturase