NF-κB inhibits TNF-induced accumulation of ROS that mediate prolonged MAPK activation and necrotic cell death
NF-κB inhibits TNF-induced accumulation of ROS that mediate prolonged MAPK activation and necrotic cell death
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DOI：
10.1093/emboj/cdg379
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发表时间：
2003-08-01
期刊：
影响因子：
11.4
通讯作者：
Nakano, H
中科院分区：
文献类型：
--
作者：
Sakon, S;Xue, X;Nakano, H
NF-kappaB 下调肿瘤坏死因子 (TNF) 诱导的 c-Jun N 末端激酶 (JNK) 激活，从而促进细胞死亡，但其机制尚不完全清楚。通过使用缺乏 TNF 受体相关因子 (TRAF) 2 和 TRAF5 (DKO) 或 p65 NF-kappaB 亚基 (p65KO) 的小鼠胚胎成纤维细胞 (MEF)，我们在此证明 TNF 刺激会导致活性氧 (ROS) 的积累，这对于延长丝裂原激活蛋白激酶 (MAPK) 激活和细胞死亡至关重要。有趣的是，通过电子显微镜和流式细胞术评估，垂死的细胞显示出坏死和凋亡的形态变化，并且抗氧化剂基本上抑制了坏死但不是凋亡的细胞死亡。重要的是，TNF 在野生型 MEF 中不会诱导 ROS 积累或延长 MAPK 激活，表明 TRAF 介导的 NF-kappaB 激活通常会抑制 TNF 诱导的 ROS 积累，从而诱导延长 MAPK 激活和坏死细胞死亡。
NF-kappaB downregulates tumor necrosis factor (TNF)-induced c-Jun N-terminal kinase (JNK) activation that promotes cell death, but the mechanism is not yet fully understood. By using murine embryonic fibroblasts (MEFs) that are deficient in TNF receptor-associated factor (TRAF) 2 and TRAF5 (DKO) or p65 NF-kappaB subunit (p65KO), we demonstrate here that TNF stimulation leads to accumulation of reactive oxygen species (ROS), which is essential for prolonged mitogen-activated protein kinase (MAPK) activation and cell death. Interestingly, dying cells show necrotic as well as apoptotic morphological changes as assessed by electron microscopy and flow cytometry, and necrotic, but not apoptotic, cell death is substantially inhibited by antioxidant. Importantly, TNF does not induce ROS accumulation or prolonged MAPK activation in wild-type MEFs, indicating that TRAF-mediated NF-kappaB activation normally suppresses the TNF-induced ROS accumulation that subsequently induces prolonged MAPK activation and necrotic cell death.