Interleukin-6-induced STAT3 and AP-1 amplify hepatocyte nuclear factor 1-mediated transactivation of hepatic genes, an adaptive response to liver injury
Interleukin-6-induced STAT3 and AP-1 amplify hepatocyte nuclear factor 1-mediated transactivation of hepatic genes, an adaptive response to liver injury
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DOI：
10.1128/mcb.21.2.414-424.2001
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发表时间：
2001-01-01
影响因子：
5.3
通讯作者：
Tau, R
中科院分区：
文献类型：
--
作者：
Leu, JI;Crissey, MAS;Tau, R
在肝损伤或应激后，致炎性和急性期反应基因迅速上调，以恢复代谢稳态并限制组织损伤。肝脏限制性胰岛素样生长因子结合蛋白1（IGFBP-1）基因的调节被代谢状态和肝切除术的变化显著改变，因此它提供了一个适当的报告，以评估在修复和再生过程中的肝脏转录环境。细胞因子白细胞介素-6（IL-6）是肝脏再生和修复所必需的，它通过未知的机制在肝脏生长期间转录上调大量基因。IL-6转基因动物和非禁食动物注射IL-6后肝脏IGFBP-1表达增加，以及切除术后IL-6（-/-）肝脏IGFBP-1表达减少，证明了IL-6在IGFBP-1上调中的生物学作用。在肝细胞和非肝细胞中，IL-6介导的IGFBP-1启动子激活是通过完整的肝细胞核因子1（HNF-1）位点，并依赖于内源性肝因子HNF-1和诱导因子STAT 3和AP-1（c-Fos/c-Jun）的存在。IL-6通过STAT 3途径起作用，因为显性负性STAT 3通过HNF-1位点完全阻断IL-6介导的IGFBP-1启动子刺激。HNF-1/c-Fos和HNF-1/STAT 3蛋白复合物在小鼠肝脏和过表达STAT 3/c-Fos/HNF-1的肝和非肝细胞系中检测到。使用葡萄糖-6-磷酸酶和α-纤维蛋白原启动子证明了类似的调节，表明HNF-1/IL-6/STAT 3/AP-1介导的肝基因表达的反式激活是肝损伤后的普遍现象。这些结果表明，这两类转录因子，生长诱导（STAT 3和AP-1）和组织特异性（HNF-1），可以相互作用，作为一种适应性反应肝损伤，以放大肝基因的表达，重要的是在器官修复过程中的稳态反应。
Following hepatic injury or stress, gluconeogenic and acute-phase response genes are rapidly upregulated to restore metabolic homeostasis and limit tissue damage. Regulation of the liver-restricted insulin-like growth factor binding protein 1 (IGFBP-1) gene is dramatically altered by changes in the metabolic state and hepatectomy, and thus it provided an appropriate reporter to assess the transcriptional milieu in the liver during repair and regeneration. The cytokine interleukin-6 (IL-6) is required for liver regeneration and repair, and it transcriptionally upregulates a vast array of genes during liver growth by unknown mechanisms. Evidence for a biologic role of IL-6 in IGFBP-1 upregulation was demonstrated by increased expression of hepatic IGFBP-1 in IL-6 transgenic and following injection of IL-6 into nonfasting animals and its reduced expression in IL-6(-/-) livers posthepatectomy. In both hepatic and nonhepatic cells, IL-6 -mediated IGFBP-1 promoter activation was via an intact hepatocyte nuclear factor 1 (HNF-1) site and was dependent on the presence of endogenous liver factor HNF-1 and induced factors STAT3 and AP-1 (c-Fos/c-Jun). IL-6 acted through the STAT3 pathway, as dominant negative STAT3 completely blocked IL-6-mediated stimulation of the IGFBP-1 promoter via the HNF-1 site. HNF-1/c-Fos and HNF-1/STAT3 protein complexes were detected in mouse livers and in hepatic and nonhepatic cell lines overexpressing STAT3/c-Fos/HNF-1. Similar regulation was demonstrated using glucose-6-phosphatase and a-fibrinogen promoters, indicating that HNF-1/IL-6/ STAT3/AP-1-mediated transactivation of hepatic gene expression is a general phenomenon after liver injury. These results demonstrate that the two classes of transcription factors, growth induced (STAT3 and AP-1) and tissue specific (HNF-1), can interact as an adaptive response to liver injury to amplify expression of hepatic genes important for the homeostatic response during organ repair.