TNFalpha and reactive oxygen species in necrotic cell death.

Death receptors, including the TNF receptor-1 (TNF-RI), have been shown to be able to initiate caspase-independent cell death. This form of "necrotic cell death" appears to be dependent on the generation of reactive oxygen species. Recent data have indicated that superoxide generation is dependent on the activation of NADPH oxidases, which form a complex with the adaptor molecules RIP1 and TRADD. The mechanism of superoxide generation further establishes RIP1 as the central molecule in ROS production and cell death initiated by TNFalpha and other death receptors. A role for the sustained JNK activation in necrotic cell death is also suggested. The sensitization of virus-infected cells to TNFalpha indicates that necrotic cell death may represent an alternative cell death pathway for clearance of infected cells.