Hisahara S, Shoji S, Okano H, Miura M
Department of Molecular Neurobiology, Institute of Basic Medical Sciences, and Center for TARA, University of Tsukuba, Ibaraki, Japan.
J Neurochem. 1997 Jul;69(1):10-20. doi: 10.1046/j.1471-4159.1997.69010010.x.
Tumor necrosis factor (TNF) is thought to be one of the mediators responsible for the damage of oligodendrocytes (OLGs) in multiple sclerosis (MS). We report here the involvement of the interleukin 1beta-converting 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 the number of live OLGs in 72 h. DNA fragmentation was detected in TNF-treated OLGs at 36 h with the terminal deoxynucleotidyl transferase dUTP nick end-labeling assay. Benzyloxycarbonyl-Asp-CH2OC(O)-2,6-dichlorobenzene, an inhibitor of the ICE/CED-3 family that shows p35-like inhibitory specificity, protected against the TNF-induced cell death of OLGs. Furthermore, acetyl-YVAD-CHO (a specific inhibitor of ICE-like proteases) as well as acetyl-DEVD-CHO (a specific inhibitor of CPP32-like proteases) enhanced the survival of OLGs treated with TNF-alpha, indicating that ICE- and the CPP32-mediated cell death pathways are activated in TNF-induced OLG cell death. Our results suggest that the inhibition of ICE/CED-3 proteases may be a novel approach to treat neurodegenerative diseases such as MS.
肿瘤坏死因子（TNF）被认为是导致多发性硬化症（MS）中少突胶质细胞（OLGs）损伤的介质之一。我们在此报告白细胞介素1β转换酶（ICE）/秀丽隐杆线虫基因ced-3（CED-3）家族参与TNF介导的OLGs细胞死亡。向表达ice和cpp32的OLGs原代培养物中添加TNF-α，在72小时内显著减少了存活的OLGs数量。在36小时时，用末端脱氧核苷酸转移酶dUTP缺口末端标记法在TNF处理的OLGs中检测到DNA片段化。苄氧羰基-Asp-CH2OC（O）-2,6-二氯苯是一种具有p35样抑制特异性的ICE/CED-3家族抑制剂，可保护OLGs免受TNF诱导的细胞死亡。此外，乙酰-YVAD-CHO（一种ICE样蛋白酶的特异性抑制剂）以及乙酰-DEVD-CHO（一种CPP32样蛋白酶的特异性抑制剂）提高了用TNF-α处理的OLGs的存活率，表明在TNF诱导的OLGs细胞死亡中，ICE和CPP32介导的细胞死亡途径被激活。我们的结果表明，抑制ICE/CED-3蛋白酶可能是治疗诸如MS等神经退行性疾病的一种新方法。
