Interleukin-6 represses the transcription of the CCAAT/enhancer binding protein-α gene in hepatoma cells by inhibiting its ability to autoactivate the proximal promoter region
Interleukin-6 represses the transcription of the CCAAT/enhancer binding protein-α gene in hepatoma cells by inhibiting its ability to autoactivate the proximal promoter region
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DOI：
10.1093/nar/gkg861
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发表时间：
2003-12-01
影响因子：
14.9
通讯作者：
Ramji, DP
中科院分区：
文献类型：
--
作者：
Foka, P;Irvine, SA;Ramji, DP
细胞因子白细胞介素-6（IL-6）在免疫和炎症反应、急性期反应和造血中起着关键作用。IL-6的这种生物学作用的特征在于基因转录的激活和抑制。不幸的是，与基因激活相反，IL-6抑制转录的机制在很大程度上仍不清楚。因此，我们已经研究了这方面使用非洲爪蟾CCAAT/增强子结合蛋白-α（C/EBPalpha）基因启动子作为模型。我们表明，通过瞬时转染实验的各种启动子荧光素酶DNA构建到肝癌细胞中的C/EBP识别序列的近端启动子区域是必不可少的IL-6介导的镇压。电泳迁移率变动分析表明，C/EBPalpha是主要的蛋白质，结合到这个网站，并与其表达模式一致，结合减少时，细胞暴露于IL-6。共转染试验首次揭示，当细胞与IL-6孵育时，C/EBPalpha而不是C/EBPbeta或Sp1反式激活启动子的能力显著降低。因此，这些研究鉴定了IL-6介导的基因转录抑制的新机制，其涉及C/EBPa介导的活化的减少。
The cytokine interleukin-6 (IL-6) plays key roles in the immune and inflammatory responses, acute-phase reaction and hematopoiesis. Such biological actions of IL-6 are characterised by both the activation and the inhibition of gene transcription. Unfortunately, in contrast to gene activation, the mechanism by which IL-6 suppresses transcription remains largely unclear. We have, therefore, investigated this aspect using the Xenopus laevis CCAAT/enhancer binding protein-alpha (C/EBPalpha) gene promoter as a model. We show by transient transfection assays of various promoter-luciferase DNA constructs into hepatoma cells that a C/EBP recognition sequence in the proximal promoter region is essential for the IL-6-mediated repression. Electrophoretic mobility shift assays showed that C/EBPalpha was the major protein that bound to this site and, consistent with its expression pattern, the binding was reduced when the cells were exposed to IL-6. Co-transfection assays revealed for the first time that the ability of C/EBPalpha, but not C/EBPbeta or Sp1, to transactivate the promoter was decreased dramatically when the cells were incubated with IL-6. These studies, therefore, identify a novel mechanism for IL-6-mediated repression of gene transcription that involves a reduction in C/EBPalpha-mediated activation.