ICE CED-3 FAMILY EXECUTES OLIGODENDROCYTE APOPTOSIS BY TUMOR-NECROSIS-FACTOR/

Tumor necrosis factor (TNF) is thought to be one of the mediators resp onsible for the damage of oligodendrocytes (OLGs) in multiple sclerosi s (MS), We report here the involvement of the interleukin 1 beta-conve rting enzyme (ICE)/Caenorhabditis elegans gene ced-3 (CED-3) family in TNF-mediated cell death of OLGs. The addition of TNF-alpha to primary cultures of OLGs that express ice and cpp32 significantly decreased t he number of live OLGs in 72 h. DNA fragmentation was detected in TNF- treated OLGs at 36 h with the terminal deoxynucleotidyl transferase dU TP nick end-labeling assay. enzyloxycarbonyl-Asp-CH2OC(O)-2,6-dichloro benzene, an inhibitor of the ICE/CED-3 family that shows p35-like inhi bitory specificity, protected against the TNF-induced cell death of OL Gs. Furthermore, acetyl-YVAD-CHO (a specific inhibitor of ICE-like pro teases) as well as acetyl-DEVD-CHO (a specific inhibitor of CPP32-like proteases) enhanced the survival of OLGs treated with TNF-alpha, indi cating that ICE- and the CPP32-medialed cell death pathways are activa ted in TNF-induced OLG cell death. Our results suggest that the inhibi tion of ICE/CED-3 proteases may be a novel approach to treat neurodege nerative diseases such as MS.