Role of caspase-1 subfamily in cytotoxic cytokine-induced oligodendrocyte cell death

Oligodendrocytes are myelin forming cells in mammalian central nervous syst em. About 50% of oligodendrocytes (OLGs) undergo cell death in normal devel opment. In addition, OLG cell deaths have been observed in demyelinating di seases including multiple sclerosis (MS). Clinical observations and in vitr o cell culture studies have suggested that cytokines mediate OLG cell damag e in multiple sclerosis (MS). Among the cytokines, tumor necrosis factor (T NF) is thought to be one of the mediators responsible for the damage of OLG s in MS. The administration of TNF-alpha to primary cultures of OLGs induce d DNA fragmentation, and significantly decreased the number of live OLGs. C hemical inhibitors Ac-YVAD-CHO (a specific inhibitor of caspase-1 (ICE)-lik e proteases) enhanced the survival of TNF-alpha treated OLGs better than Ac -DEVD-CHO (a specific inhibitor of caspase-3 (CPP32)-like proteases). These results indicate that caspase-1-mediated cell-death pathway are activated in TNF-induced OLG cell death. Caspase-11 is involved in activation of casp ase-1. Oligodendrocytes from caspase-11-deficient mice are partially resist ant to TNF-induced OLG cell death. Our results suggest that the inhibition of caspase-1 sufamily may be a novel therapeutic approach to treat MS.