Involvement of caspases in cytotoxic cytokine-mediated oligodendrocyte cell death

Oligodendrocytes are myelin-forming cells in the mammalian central nervous system. About 50% of oligodendrocytes undergo cell death in normal developm ent. In addition, massive oligodendrocyte cell death has been observed in m ultiple sclerosis. Tumor necrosis factor (TNF) is thought to be one of the mediators responsible for the damage of oligodendrocytes in multiple sclero sis. The addition of TNF-alpha to primary cultures of oligodendrocytes sign ificantly decreased the number of live cells in 72 h. DNA fragmentation was detected in TNF-treated oligodendrocytes at 36 h by TUNEL assay. Chemical inhibitors Ac-YVAD-CHO (a specific inhibitor of caspase-1 [ICE]-like protea ses) as well as Ac-DEVD-CHO (a specific inhibitor of caspase-3[CPP32]-like proteases) enhanced the survival of oligodendrocytes treated with TNF-alpha , indicating that caspase-1- and the caspase-3-mediated cell-death pathways are activated in TNF-induced oligodendrocyte cell death. Caspase-11 is inv olved in activation of caspase-1. Oligodendrocytes from CASP-11-deficient m ice are partially resistant to TNF-induced oligodendrocyte cell death. Our results suggest that the inhibition of caspases may be a novel approach to treat multiple sclerosis.