It has been proposed that ceramide acts as a cellular messenger to mediate tumor necrosis factor- (TNF-)-induced apoptosis. Based on this hypothesis, it was postulated that resistance of some cells to TNF- cytotoxicity was due to an insufficient production of ceramide on stimulation by TNF-. The present study was initiated to investigate whether this was the case in mesangial cells, which normally are insensitive to TNF--induced apoptosis. Our results indicate that although C₂ ceramide was toxic to mesangial cells, the cell death it induced differed both morphologically and biochemically from that induced by TNF- in the presence of cycloheximide (CHX). The most apparent effect of C₂ ceramide was to cause cells to swell, followed by disruption of the cell membrane. It is evident that C₂ ceramide caused cell death by necrosis, whereas TNF- in the presence of CHX killed the cells by apoptosis. C₂ ceramide did not mimic the effects of TNF- on the activation of c-Jun NH₂-terminal protein kinase and nuclear factor-B transcription factor. Although mitogen-activated protein kinase [extracellular signal-related kinase (ERK)] was activated by both C₂ ceramide and TNF-, such activation appeared to be mediated by different mechanisms as judged from the kinetics of ERK activation. Furthermore, the cleavage of cytosolic phospholipase A₂ during cell death induced by C₂ ceramide and by TNF- in the presence of CHX showed distinctive patterns. The present study provides evidence that apoptosis and necrosis use distinctive signaling machinery to cause cell death.

apoptosis; mitogen-activated protein kinase; c-Jun NH₂-terminal protein kinase; nuclear factor-B

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