TUMOR NECROSIS FACTOR-INDUCED APOPTOSIS IS MEDIATED BY A CRMA-SENSITIVE CELL-DEATH PATHWAY

We report here that the activation of the interleukin 1 beta (IL-1 bet a)-converting enzyme (ICE) family is likely to be one of the crucial e vents of tumor necrosis factor (TNF) cytotoxicity, The cowpox virus Cr mA protein, a member of the serpin superfamily, inhibits the enzymatic activity of ICE and ICE-mediated apoptosis, HeLa cells overexpressing crmA are resistant to apoptosis induced by Ice but not by Ich-1, anot her member of the Ice/ced-3 family of genes, We found that the CrmA-ex pressing HeLa cells are resistant to TNF-alpha/cycloheximide (CHX)-ind uced apoptosis, Induction of apoptosis in HeLa cells by TNF-alpha/CHX is associated with secretion of mature IL-1 beta, suggesting that an I L-1 beta-processing enzyme, most likely ICE itself, is activated by TN F-alpha/CHX stimulation. These results suggest that one or more member s of the ICE family sensitive to CrmA inhibition are activated and pla y a critical role in apoptosis induced by TNF.