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 beta)-converting enzyme (ICE) family is likely to be one of the crucial events of tumor necrosis factor (TNF) cytotoxicity. The cowpox virus CrmA 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, another member of the Ice/ced-3 family of genes. We found that the CrmA-expressing HeLa cells are resistant to TNF-alpha/cycloheximide (CHX)-induced apoptosis. Induction of apoptosis in HeLa cells by TNF-alpha/CHX is associated with secretion of mature IL-1 beta, suggesting that an IL-1 beta-processing enzyme, most likely ICE itself, is activated by TNF-alpha/CHX stimulation. These results suggest that one or more members of the ICE family sensitive to CrmA inhibition are activated and play a critical role in apoptosis induced by TNF.
Miura
M
M
Cardiovascular Research Center, Massachusetts General Hospital-East, Charlestown 02129, USA.
Friedlander
R M
RM
Yuan
J
J
D017209:Apoptosis / Q000187:drug effects*; D003001:Cloning, Molecular; D003513:Cycloheximide / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D015843:Serpins / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014764:Viral Proteins
D015843:Serpins; D014409:Tumor Necrosis Factor-alpha; D014764:Viral Proteins; C074641:interleukin-1beta-converting enzyme inhibitor; D003513:Cycloheximide