TNFα-induced IEC-6 cell apoptosis requires activation of ICE caspases whereas complete inhibition of the caspase cascade leads to necrotic cell death

Tumor necrosis factor (TNF)alpha is considered to play a key pathogenetic role in inflammatory bowel diseases. In this study we analyzed the mechanisms by which TNF alpha induces intestinal epithelial cell apoptosis. TNF alpha alone, and more potently in combination with IFN gamma, induced a high degree of IEC-6 cell apoptosis. This effect was more than 100-fold stronger if both of the TNF-R were stimulated, compared to stimulation of the p55-TNF-R alone, indicating an important apoptosis enhancing effect of the p75-TNF-R. TNF alpha-induced apoptosis required activation of ICE caspases and was completely abolished by its inhibitor, zVAD-fmk. Specific inhibition of caspase-3 with zDEVD-fmk did not alter the effect of TNF alpha. Western blot analyses confirmed that caspase-3 was not activated in response to TNF alpha. In the presence of complete inhibition of the caspase cascade with zVAD-fmk (greater than or equal to 50 mu M), TNF alpha induced cell necrosis rather than apoptosis. Our data reveal that TNF alpha can trigger enterocyte cell death via apoptosis or necrosis, depending upon the activation or blockade of specific caspases. (C) 1999 Academic Press.