Induction of oligodendrocyte apoptosis by C2-ceramide.

Tumor necrosis factor-alpha induces oligodendrocytes apoptosis, and is known to stimulate the hydrolysis of sphingomyelin to form the lipid mediator, ceramide. These data encouraged us to determine whether ceramide itself is able to induce apoptosis in oligodendrocytes. For this purpose the cell-permeable ceramide analog, C2-ceramide was used. Treatment of bovine oligodendrocyte cell cultures with this compound induced cell death in a time- and concentration-dependent manner. The induction of cell death was specifically associated with the action of C2-ceramide and could not be elicited by dioctanoylglycerol (DC8) or phorbol 12-myristate 13-acetate (PMA). Treatment of the cultures with neutral sphingomyelinase, which increased the hydrolyses of endogenous sphingomyelin, resulted in oligodendrocyte death, whereas exposure of the cells to phospholipase C and A2 did not. C2-ceramide treatment caused DNA fragmentation. Morphologic analysis of the cells showed that C2-ceramide treatment resulted in a loss of their processes, reduction of cell volume, chromatin condensation, and formation of apoptotic bodies. These results indicate that ceramide can induce oligodendrocyte apoptosis, and suggest that sphingolipid metabolism plays a key role in the regulation of this process.