TNF receptor superfamily-induced cell death: redox-dependent execution

Tumor necrosis factor (TNF) superfamily is a group of cytokines with important functions in immunity, inflammation, differentiation, control of cell proliferation, and apoptosis. TNF alpha is the founding member of the 19 different proteins that have so far been identified within this family. TNF family members exert their biological effects through the TNF receptor (TNFR) superfamily of cell surface receptors that share a stretch of similar to 80 amino acids within their cytoplasmic region, the death domain (DD), critical for recruiting the death machinery. Work over the last decade has unraveled critical signaling networks involved in TNFR-induced cell death, specifically using the constitutively expressed TNFR1 as a prototype. Of particular interest is the intermediary role of intracellular reactive oxygen species (ROS) in signal transduction after ligation of the TNFR1. With the increasing understanding of the of death receptor signaling pathways, the exact role of ROS in TNF alpha-induced execution is now believed to be far more complicated than originally thought. Recently, some important discoveries have underscored the critical role of ROS in TNF alpha signaling, notably in TNF alpha-mediated activation of nuclear factor-kappa B (NF-kappa B) and c-Jun N-terminal kinase (c-Jun NH2-terminal kinase, JNK), as well as in cell death (apoptotic and necrotic) pathways. Here we attempt to review the existing knowledge on the involvement of ROS in death receptor signaling using TNF alpha-TNFR1 as the model system, specifically addressing the involvement of intracellular ROS in TNF alpha-induced cell death and in TNF alpha-induced activation of NF-kappa B and JNK and their crosstalk. Shen, H-M., Pervaiz, S. TNF receptor superfamily-induced cell death: redox-dependent execution.