Nakajima Akihito, Komazawa-Sakon Sachiko, Takekawa Mutsuhiro, Sasazuki Tomonari, Yeh Wen-Chen, Yagita Hideo, Okumura Ko, Nakano Hiroyasu
Department of Immunology, Juntendo University School of Medicine, Tokyo, Japan.
EMBO J. 2006 Nov 29;25(23):5549-59. doi: 10.1038/sj.emboj.7601423. Epub 2006 Nov 16.
Inhibition of NF-kappaB activation increases susceptibility to tumor necrosis factor (TNF)alpha-induced cell death, concurrent with caspases and prolonged c-Jun N-terminal kinase (JNK) activation, and reactive oxygen species (ROS) accumulation. However, the detailed mechanisms are unclear. Here we show that cellular FLICE-inhibitory protein (c-FLIP) is rapidly lost in NF-kappaB activation-deficient, but not wild-type fibroblasts upon TNFalpha stimulation, indicating that NF-kappaB normally maintains the cellular levels of c-FLIP. The ectopic expression of the long form of c-FLIP (c-FLIPL) inhibits TNFalpha-induced prolonged JNK activation and ROS accumulation in NF-kappaB activation-deficient fibroblasts. Conversely, TNFalpha induces prolonged JNK activation and ROS accumulation in c-Flip-/- fibroblasts. Moreover, c-FLIPL directly interacts with a JNK activator, MAP kinase kinase (MKK)7, in a TNFalpha-dependent manner and inhibits the interactions of MKK7 with MAP/ERK kinase kinase 1, apoptosis-signal-regulating kinase 1, and TGFbeta-activated kinase 1. This stimuli-dependent interaction of c-FLIPL with MKK7 might selectively suppress the prolonged phase of JNK activation. Taken that ROS promote JNK activation and activation of the JNK pathway may promote ROS accumulation, c-FLIPL might block this positive feedback loop, thereby suppressing ROS accumulation.
抑制核因子-κB（NF-κB）激活会增加细胞对肿瘤坏死因子（TNF）α诱导的细胞死亡的易感性，同时伴有半胱天冬酶（caspases）的激活、c-Jun氨基末端激酶（JNK）的持续激活以及活性氧（ROS）的积累。然而，具体机制尚不清楚。在此我们表明，在TNFα刺激下，细胞FLICE抑制蛋白（c-FLIP）在NF-κB激活缺陷的成纤维细胞中迅速丢失，但在野生型成纤维细胞中则不然，这表明NF-κB通常维持细胞内c-FLIP的水平。c-FLIP长形式（c-FLIPL）的异位表达可抑制TNFα诱导的NF-κB激活缺陷的成纤维细胞中JNK的持续激活和ROS的积累。相反，TNFα可诱导c-Flip基因敲除的成纤维细胞中JNK的持续激活和ROS的积累。此外，c-FLIPL以TNFα依赖的方式直接与JNK激活剂丝裂原活化蛋白激酶激酶（MKK）7相互作用，并抑制MKK7与丝裂原活化蛋白激酶/细胞外信号调节激酶激酶1、凋亡信号调节激酶1和转化生长因子β激活激酶1的相互作用。c-FLIPL与MKK7的这种刺激依赖性相互作用可能选择性地抑制JNK激活的持续阶段。鉴于ROS促进JNK激活，而JNK途径的激活可能促进ROS积累，c-FLIPL可能会阻断这种正反馈回路，从而抑制ROS积累。
