IKKi/IKKε plays a key role in integrating signals induced by pro-inflammatory stimuli
IKKi/IKKε plays a key role in integrating signals induced by pro-inflammatory stimuli
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DOI：
10.1074/jbc.m303001200
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发表时间：
2003-07-18
影响因子：
4.8
通讯作者：
Ulevitch, RJ
中科院分区：
文献类型：
--
作者：
Kravchenko, VV;Mathison, JC;Ulevitch, RJ
我们报告说，编码 IKKi/IKKepsilon (IKKi) 激酶的诱导基因产物是一组受促炎刺激（如细菌内毒素（脂多糖 (LPS)））上调的基因表达所必需的。在这里，我们利用从 IKK2、p65 和 IKKi 基因缺失的小鼠中获得的小鼠胚胎成纤维细胞，提供了证据支持通过 NF-kappaB 和 CCAAA/增强子结合蛋白 (C/EBP) 途径的信号传导之间的联系。该链接包括 C/EBPbeta 和 C/EBPdelta 基因转录的 NF-kappaB 依赖性调节以及 IKKi 介导的 C/EBP 激活。 NF-kappaB 通路的破坏会导致 C/EBPbeta、C/EBPdelta 和 IKKi 基因的诱导性上调被阻断。缺乏 IKKi 的细胞在激活经典 NF-kappaB 通路方面是正常的，但无法响应 LPS 诱导 C/EBPdelta 活性以及 C/EBP 和 C/EBP-NF-kappaB 靶基因的转录。此外，我们还发现，响应 LPS 或肿瘤坏死因子 α，C/EBP 的 β 和 δ 亚基均与 IKKi 启动子相互作用，这表明调节 IKKi 依赖性细胞过程中存在反馈机制。这些数据是第一批深入了解 IKKi 生物学功能的数据。
We report that the product of the inducible gene encoding the kinase known as IKKi/IKKepsilon (IKKi) is required for expression of a group of genes up-regulated by pro-inflammatory stimuli such as bacterial endotoxin (lipopolysaccharide (LPS)). Here, using murine embryonic fibroblasts obtained from mice bearing deletions in IKK2, p65, and IKKi genes, we provide evidence to support a link between signaling through the NF-kappaB and CCAAA/enhancer-binding protein (C/EBP) pathways. This link includes an NF-kappaB-dependent regulation of C/EBPbeta and C/EBPdelta gene transcription and IKKi-mediated activation of C/EBP. Disruption of the NF-kappaB pathway results in the blockade of the inducible up-regulation of C/EBPbeta, C/EBPdelta, and IKKi genes. Cells lacking IKKi are normal in activation of the canonical NF-kappaB pathway but fail to induce C/EBPdelta activity and transcription of C/EBP and C/EBP-NF-kappaB target genes in response to LPS. In addition we show that, in response to LPS or tumor necrosis factor alpha, both beta and delta subunits of C/EBP interact with IKKi promoter, suggesting a feedback mechanism in the regulation of IKKi-dependent cellular processes. These data are among the first to provide insights into the biological function of IKKi.