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 development. In addition, massive oligodendrocyte cell death has been observed in multiple sclerosis. Tumor necrosis factor (TNF) is thought to be one of the mediators responsible for the damage of oligodendrocytes in multiple sclerosis. The addition of TNF-α to primary cultures of oligodendrocytes significantly decreased the number of live cells in 72 h. DNA fragmentation was detected in TNF-treated oligodendrocytes at 36h by TUNEL assay. Chemical inhibitors Ac-YVAD-CHO (a specific inhibitor of caspase-1[ICE]-like proteases) as well as Ac-DEVD-CHO (a specific inhibitor of caspase-3[CPP32]-like proteases) enhanced the survival of oligodendrocytes treated with TNF-α, indicating that caspase-1- and the caspase-3-mediated cell-death pathways are activated in TNF-induced oligodendrocyte cell death. Caspase-11 is involved in activation of caspase-1. Oligodendrocytes from CASP-11-deficient mice 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.