Tumor necrosis factor (TNF or TNFalpha) is a key mediator in the establishment and maintenance of multiple inflammatory and autoimmune diseases, such as rheumatoid arthritis and inflammatory bowel disease. TNF receptor signaling can simultaneously activate caspase 8, the transcription factor, NF-KappaB and the kinase, JNK. While activation of caspase 8 is required for TNF-induced apoptosis, and induction of NF-KappaB inhibits cell death, the precise function of JNK activation in TNF signaling is not clearly understood. We have shown that TNF-mediated caspase 8 cleavage and apoptosis require a sequential pathway involving JNK, Bid, and Smac/DIABLO. Activation of JNK induces caspase 8-independent cleavage of Bid at a distinct site to generate the Bid cleavage product jBid. Translocation of jBid to mitochondria leads to preferential release of Smac/DIABLO, but not cytochrome c. The released Smac/DIABLO then disrupts the TRAF2-cIAP 1 complex. We propose that the JNK pathway is required to relieve the inhibition imposed by TRAF2-cIAP1 on caspase 8 activation and induction of apoptosis. In this proposal, we will explore the signaling mechanisms underlying the choice between cell survival and cell death in TNF response. Since TNF-mediated apoptosis plays a crucial role in both physiological and pathophysiological functions of TNF, understanding the regulation of TNF response will provide new avenues of therapeutic intervention for TNF-mediated inflammatory and autoimmune diseases.
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