Involvement of de novo ceramide biosynthesis in lymphotoxin-induced oligodendrocyte death

BOTH experimental and clinical studies suggest that lymphotoxin (LT) plays an important role in multiple sclerosis (MS) by inducing oligodendrocyte (O L)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 cyt otoxic molecules, we have investigated the possible role of this second mes senger in LT-induced cytotoxicity on SV40 immortalized new-born mice OL. Hu man recombinant LT exposure (50 ng/ml) resulted in intracellular ceramide a ccumulation which peaked at 48 h (similar to 170% increase) and paralleled LT-induced cytotoxicity. Moreover, fumonisin B1, a. potent and specific cer amide synthase inhibitor, not only inhibited ceramide accumulation but also protected OL from LT cytotoxicity. These results suggest that LT-induced c eramide synthase stimulation and subsequent increased intracellular ceramid e concentration are implicated in oligodendrocyte death. NeuroReport 10:237 3-2376 (C) 1999 Lippincott Williams & Wilkins.