Regulation of Cellular Response to TNF

描述（由申请人提供）：肿瘤坏死因子（TNF或TNFalpha）是建立和维持多种炎症和自身免疫性疾病（如类风湿关节炎和炎症性肠病）的关键介质。TNF受体信号可以同时激活caspase 8，转录因子NF-KappaB和JNK激酶。虽然TNF诱导的细胞凋亡需要激活caspase 8，并且NF-KappaB的诱导可以抑制细胞死亡，但JNK激活在TNF信号传导中的确切功能尚不清楚。我们已经证明，tnf介导的caspase 8切割和凋亡需要一个涉及JNK、Bid和Smac/DIABLO的顺序通路。JNK的激活诱导了不依赖于caspase 8的Bid在不同位点的切割，生成Bid切割产物jBid。jBid转位到线粒体导致Smac/DIABLO优先释放，而不是细胞色素c。释放的Smac/DIABLO随后破坏TRAF2-cIAP 1复合物。我们认为JNK通路是解除TRAF2-cIAP1对caspase 8激活和诱导凋亡的抑制所必需的。在本研究中，我们将探讨TNF反应中细胞存活和细胞死亡选择的信号机制。由于TNF介导的细胞凋亡在TNF的生理和病理生理功能中都起着至关重要的作用，了解TNF反应的调控将为TNF介导的炎症和自身免疫性疾病的治疗干预提供新的途径。

DESCRIPTION (provided by applicant): 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.