Interleukin-6 inhibits human peroxisome proliferator activated receptor alpha gene expression via CCAAT/enhancer-binding proteins in hepatocytes
Interleukin-6 inhibits human peroxisome proliferator activated receptor alpha gene expression via CCAAT/enhancer-binding proteins in hepatocytes
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DOI：
10.1016/j.biocel.2007.05.015
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发表时间：
2007-01-01
影响因子：
4
通讯作者：
Tengku-Muhammad, Tengku Sifzizul
中科院分区：
文献类型：
--
作者：
Chew, Choy-Hoong;Chew, Guat-Siew;Tengku-Muhammad, Tengku Sifzizul
过氧化物酶体增殖物激活受体α被认为是肝细胞中急性期反应基因的调节因子。白细胞介素-6被广泛认为是一种主要的细胞因子，负责调节急性期蛋白，因此，急性期反应。不幸的是，到目前为止，很少有人了解白细胞介素-6调节过氧化物酶体增殖物激活受体α基因表达的分子机制。在这里，我们报告的分子机制，其中过氧化物酶体增殖物激活受体α调节白细胞介素-6在人HepG 2细胞。白细胞介素-6在基因转录水平下调过氧化物酶体增殖物激活受体α基因表达。人类过氧化物酶体增殖物激活受体α启动子B的功能解剖揭示了预测的CCAAT/增强子结合蛋白结合位点的作用（-164/+34）介导白细胞介素-6对过氧化物酶体增殖物激活受体α mRNA表达的抑制作用，电泳迁移率变动分析显示，在白细胞介素-6-HepG 2细胞。然后，共转染实验证明，CCAAT/增强子结合蛋白β与CCAAT/增强子结合蛋白α和CCAAT/增强子结合蛋白δ的同源二聚体或异源二聚体在抑制过氧化物酶体增殖物激活受体α启动子B的转录活性中起主要作用，从而降低过氧化物酶体增殖物激活受体α mRNA的表达。因此，这些研究表明，白细胞介素-6介导的过氧化物酶体增殖物激活受体α基因表达抑制的一种新机制，涉及CCAAT/增强子结合蛋白β激活CCAAT/增强子结合蛋白亚型可能起主要作用。(c)2007爱思唯尔有限公司保留所有权利。
Peroxisome proliferator activated receptor alpha has been implicated as a regulator of acute phase response genes in hepatocytes. Interleukin-6 is widely known as a major cytokine responsible in the regulation of acute phase proteins and, therefore, acute phase response. Unfortunately, to date, very little is understood about the molecular mechanisms by which interleukin-6 regulates the gene expression of peroxisome proliferator activated receptor alpha. Here, we report the molecular mechanisms by which peroxisome proliferator activated receptor alpha was regulated by interleukin-6 in human HepG2 cells. Interleukin-6 was shown to down-regulate the peroxisome proliferator activated receptor alpha gene expression at the level of gene transcription. Functional dissection of human peroxisome proliferator activated receptor alpha promoter B revealed the role of predicted CCAAT/enhancer-binding protein binding site (-164/+34) in mediating the interleukin-6 inhibitory effects on peroxisome proliferator activated receptor alpha mRNA expression and electrophoretic mobility shift assay showed the binding of CCAAT/enhancer-binding protein isoforms to this cis-acting elements was increased in interleukin-6-treated HepG2 cells. Co-transfection experiments, then, demonstrated that CCAAT/enhancer-binding protein beta either in homodimer or heterodimer with CCAAT/enhancer-binding protein alpha and CCAAT/enhancer-binding protein delta plays a predominant role in inhibiting the transcriptional activity of peroxisome proliferator activated receptor alpha promoter B, thus, reducing the peroxisome proliferator activated receptor alpha mRNA expression. These studies, therefore, suggest a novel mechanism for interleukin-6-inediated inhibition of peroxisome proliferator activated receptor alpha gene expression that involves the activation of CCAAT/enhancer-binding protein isoforms with CCAAT/enhancer-binding protein beta may play a major role. (c) 2007 Elsevier Ltd. All rights reserved.