Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, 60637, USA.
The Second Affiliated Hospital, The State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Allery & Clinical Immunology, Guangzhou Medical University, Guangzhou, Guangdong, 510260, China.
Cell Res. 2018 Jul;28(7):701-718. doi: 10.1038/s41422-018-0041-7. Epub 2018 May 24.
The inflammatory cytokine TNFα plays a crucial role in the pathology of many inflammatory and infectious diseases. However, the mechanism underlying TNFα cytotoxicity in these diseases is incompletely understood. Here we report that the pro-apoptotic BCL-2 family member BAD mediates TNFα cytotoxicity despite concurrent activation of IKK and NF-κB in vitro by inducing apoptosis in cultured cells and in vivo by eliciting tissue damage of multiple organs and contributing to mortality in septic shock. At high doses, TNFα significantly inactivates RhoA through activation of the Src-p190GAP pathway, resulting in massive actin stress fiber destabilization, followed by substantial BAD release from the cytoskeleton to the cytosol. Under this condition, activated IKK fails to phosphorylate all cytosolic BAD, allowing translocation of non-phosphorylated BAD to mitochondria to trigger apoptosis. Polymicrobial infection utilizes the same mechanism as high-dose TNFα to elicit apoptosis-associated tissue damage of multiple organs. Consequently, loss of Bad or elimination of BAD pro-apoptotic activity protects mice from tissue damage of multiple organs and reduces mortality rates. Our results support a model in which BAD mediates TNFα cytotoxicity despite concurrent activation of the IKK-NF-κB pathway in cultured mammalian cells and in septic shock.
炎症细胞因子 TNFα 在许多炎症和感染性疾病的病理学中起着至关重要的作用。然而，在这些疾病中，TNFα 细胞毒性的机制尚未完全阐明。在这里，我们报告了促凋亡 BCL-2 家族成员 BAD 介导 TNFα 细胞毒性，尽管在体外通过诱导培养细胞凋亡和体内通过引发多个器官的组织损伤并导致感染性休克中的死亡率来同时激活 IKK 和 NF-κB。在高剂量下，TNFα 通过激活Src-p190GAP 途径显著失活 RhoA，导致大量肌动蛋白应力纤维不稳定，随后大量 BAD 从细胞骨架释放到细胞质中。在这种情况下，激活的 IKK 无法磷酸化所有细胞质 BAD，允许非磷酸化 BAD 易位到线粒体以触发细胞凋亡。多微生物感染利用与高剂量 TNFα 相同的机制引发多个器官的凋亡相关组织损伤。因此，Bad 的缺失或 BAD 促凋亡活性的消除可保护小鼠免受多个器官的组织损伤并降低死亡率。我们的研究结果支持这样一种模型，即 BAD 介导 TNFα 细胞毒性，尽管在培养的哺乳动物细胞和感染性休克中同时激活了 IKK-NF-κB 途径。
