Tumor necrosis factor induces distinct patterns of caspase activation in WEHI-164 cells associated with apoptosis or necrosis depending on cell cyclestage

TNF is unusual among the death receptor ligands in being able to induce eit her apoptotic or necrotic cell death. We have observed that in WEHI 164 fib rosarcoma, cells the mode of TNF-induced cell death is dependent on the sta ge of the cell cycle. Cells arrested in G(0)/G(1) undergo necrosis, while t hose progressing through the cell cycle undergo apoptosis. TNF induces casp ase activity in both settings, and the broad spectrum caspase inhibitor zVA D-fmk inhibits this activity and blocks both TNF-induced apoptosis and necr osis. Inhibition of oxygen radical accumulation does not block cytotoxicity , The presence and activation of specific caspases were examined by Western blotting. The procaspase-8a isoform was down-regulated in proliferating ce lls. Procaspases-8b and -7 were cleaved during TNF-induced apoptosis but no t necrosis. Thus, a different pattern of caspase expression and activation occurs dependent on the cell cycle and which may determine the mode of cell death. (C) 1999 Academic Press.