Abstract: TNF is the known death receptor ligand which induce apoptosis and necrosis. Reactive oxygen metabolites, ceramide (synthesized de novo and as a product of sphingomyelin cycle), and caspases have been implicated as potential mediators of cell death. Their mechanistic relationship remains to be elucidated. The presence and activation of executor caspase-3 has been found to be regulated during both TNF-induced apoptosis and necrosis on their early stages. TNF-induced cell damage, suggesting the induction of both, apoptosis and necrosis, depended on the cell cycle. Necrosis induced by TNF was inhibited by denitrophenol (DNP). Pretreatment of these cells with exogenous bacterial sphingomyelinase (SMase) potentiates TNF-a induced apoptosis only, suggesting the role of ceramide from sphingomyelin cycle in TNF signaling pathways of apoptosis. DNP was found to initiate necrosis after SMase and TNF common action. The role of ceramide synthesis in enhanced ceramide generation in response to oxidant stress was shown using inhibitor of ceramide synthase - fumonisin B1. Its effect was found to be modulated by mitochondrial chain respiration inhibitors. Monoclonal antibodies to TNF-a receptors R1 and R2 exhibit the more high level of necrosis compared with TNF and both regulated by DNP and phospholipase A2. TNF-R2 effect was not found previously. Conclusion: Ceramide synthesis and sphingomyelin breakdown, caspase activation and reactive oxygen metabolites production are required for the TNF-a-induced apoptosis and necrosis which may be regulated dependently on cell cycle. TNF-initiated necrosis seems to be the disrupted apoptotic program and may be classified as aponecrosis.
Reference: Martinova E.A., Poddubskaya E.V., Polosukhina E.R., Klimova S.V., TNF-induced apoptosis and necrosis in hl-60 leukemia cells is regulated by reactive oxygen metabolites and dependent on cell cycle, Biomeditsinskaya khimiya, 2003, vol: