Redox regulation of tumor necrosis factor signaling.

Tumor necrosis factor-alpha (TNF) is a key cytokine that has been shown to play important physiologic (e.g., inflammation) and pathophysiologic (e.g., various liver pathologies) roles. In liver and other tissues, TNF treatment results in the simultaneous activation of an apoptotic pathway (i.e., TRADD, RIP, JNK) and a survival pathway mediated by NF-kappaB transcription of survival genes (i.e., GADD45beta, Mn-SOD, cFLIP). The cellular response (e.g., proliferation versus apoptosis) to TNF is determined by the balance between the apoptotic signaling pathway and the NF-kappaB survival pathway stimulated by TNF. Reactive oxygen species (ROS) are important modulators of signaling pathways and can regulate both apoptotic signaling and NF-kappaB transcription triggered by TNF. ROS are important in mediating the sustained activation of JNK, to help mediate apoptosis after TNF treatment. In some cells, ROS are second messengers that mediate apoptosis after TNF stimulation. Conversely, ROS can cause redox modifications that inhibit NF-kappaB activation, which can lead to cell death triggered by TNF. Consequently, the redox status of cells can determine the biologic response that TNF will induce in cells. In many liver pathologies, ROS generated extrinsically (e.g., inflammation) or intrinsically (i.e., drugs, toxins) may act in concert with TNF to promote hepatocyte death and liver injury through redox inhibition of NF-kappaB.