Death receptor-induced apoptotic and necrotic cell death: differential role of caspases and mitochondria

In L929sAhFas cells, tumor necrosis factor (TNF) leads to necrotic cell dea th, whereas agonistic anti-fas antibodies elicit apoptotic cell death. Apop tosis, but not necrosis, is correlated with a rapid externalization of phos phatidylserine and the appearance of a hypoploid population. During necrosi s no cytosolic and organelle-associated active caspase-3 and -7 fragments a re detectable. The necrotic process does not involve proteolytic generation of truncated Bid; moreover, no mitochondrial release of cytochrome c is ob served, Bcl-2 overexpression slows down the onset of necrotic cell death. I n the case of apoptosis, active caspases are released to the culture supern atant, coinciding with the release of lactate dehydrogenase, Following necr osis, mainly unprocessed forms of caspases are released. Both TNF-induced n ecrosis and necrosis induced by anti-Fas in the presence of the caspase inh ibitor benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone are prevented by the serine protease inhibitor N-tosyl-L-phenylalanine chloromethylketone and the oxygen radical scavenger butylated hydroxyanisole, while Fas-induc ed apoptosis is not affected.