Regulation of Cellular Response to TNF

肿瘤坏死因子(TNF或TNFcz)是多发性硬化形成和维持的关键介质。 炎症性和自身免疫性疾病，如类风湿性关节炎和炎症性肠病。肿瘤坏死因子- 受体信号可以同时激活转录因子caspase8、核因子-kB和蛋白激酶JNK。 而caspase8的激活是肿瘤坏死因子诱导的细胞凋亡所必需的，而核因子Rd3的诱导则抑制细胞 死亡，JNK激活在肿瘤坏死因子信号转导中的确切作用尚不清楚。我们已经证明了 肿瘤坏死因子介导的caspase8裂解和细胞凋亡需要一条涉及JNK、BID和 SMAC/Diablo。JNK的激活诱导不依赖于caspase 8的Bid在不同的位点切割 生成竞价分割产品jBid。JBid易位到线粒体导致优先释放 Smac/Diablo，但不是细胞色素c。释放的Smac/Diablo随后扰乱TRAF2-CIAP 1 很复杂。我们认为，需要JNK途径来解除TRAF2-cIAP1的抑制作用 关于caspase8的激活和诱导细胞凋亡。在本提案中，我们将探讨信令 在肿瘤坏死因子反应中选择细胞存活和细胞死亡的机制。因为肿瘤坏死因子- 介导的细胞凋亡在肿瘤坏死因子的生理和病理生理功能中起着至关重要的作用。 了解肿瘤坏死因子反应的调节机制将为肿瘤坏死因子的治疗干预提供新的途径。 介导性炎症和自身免疫性疾病。

Tumor necrosis factor (TNF or TNFcz) is a key mediator in the establishment and maintenance of multiple inflammatory and autoimmue diseases, such as rheumatoid arthritis and inflammatory bowl disease. TNF- receptor signaling can simultaneously activate caspase 8, the transcription factor, NF-KB and the kinase, JNK. While activation of caspase 8 is required for TNF-induced apoptosis, and induction of NF-rd3 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 ofjBid 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 autoimmue diseases.