Inhibition of JNK activation through NF-κB target genes
Inhibition of JNK activation through NF-κB target genes
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DOI：
10.1038/35104568
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发表时间：
2001-11-15
期刊：
影响因子：
64.8
通讯作者：
Lin, A
中科院分区：
文献类型：
--
作者：
Tang, GL;Minemoto, Y;Lin, A
促炎细胞因子肿瘤坏死因子-α（TNF-α）调节免疫应答、炎症和程序性细胞死亡（细胞凋亡）（1-4）。暴露于TNF-α的细胞的最终命运由其不同效应子之间的信号整合决定，包括I κ B激酶（IKK）、c-Jun N-末端蛋白激酶（JNK）和半胱天冬酶（1）。凋亡性细胞死亡需要激活半胱天冬酶（5），而IKK激活通过转录因子NF-kappaB抑制细胞凋亡，其靶基因包括半胱天冬酶抑制剂（1，6 -10）。JNK激活转录因子c-Jun/AP-1以及其他靶标（11-16）。然而，JNK活化在TNF-α诱导的细胞凋亡中的作用尚不清楚（17，18）。目前还不清楚IKK和JNK之间是否发生任何串扰，如果是这样，它如何影响TNF-α诱导的细胞凋亡。我们使用IKK复合物的IKK β催化亚基或NF-κ B的RelA/p65亚基缺陷的鼠胚胎成纤维细胞对此进行了研究。在这里，我们发现除了抑制半胱天冬酶，IKK/NF-κ B通路还部分通过NF-κ B诱导的X染色体连锁凋亡抑制剂（XIAP）负性调节TNF-α介导的JNK活化（7，9）。这种对TNF-α信号传导特异性的负串扰，不影响白细胞介素-1（IL-1）对JNK的激活，有助于抑制细胞凋亡。
The proinflammatory cytokine tumour necrosis factor-alpha (TNF-alpha) regulates immune responses, inflammation and programmed cell death (apoptosis)(1-4). The ultimate fate of a cell exposed to TNF-alpha is determined by signal integration between its different effectors, including I kappaB kinase (IKK), c-Jun N-terminal protein kinase (JNK) and caspases(1). Activation of caspases is required for apoptotic cell death(5), whereas IKK activation inhibits apoptosis through the transcription factor NF-kappaB, whose target genes include caspase inhibitors(1,6-10). JNK activates the transcription factor c-Jun/AP-1, as well as other targets(11-16). However, the role of JNK activation in apoptosis induced by TNF-alpha is less clear(17,18). It is unknown whether any crosstalk occurs between IKK and JNK, and, if so, how it affects TNF-alpha -induced apoptosis. We investigated this using murine embryonic fibroblasts that are deficient in either the IKK beta catalytic subunit of the IKK complex or the RelA/p65 subunit of NF-kappaB. Here we show that in addition to inhibiting caspases, the IKK/NF-kappaB pathway negatively modulates TNF-alpha -mediated JNK activation, partly through NF-kappaB-induced X-chromosome-linked inhibitor of apoptosis (XIAP)(7,9). This negative crosstalk, which is specific to TNF-alpha signalling and does not affect JNK activation by interleukin-1 (IL-1), contributes to inhibition of apoptosis.