Interleukin-6-specific activation of the C/EBPδ gene in hepatocytes is mediated by Stat3 and Sp1
Interleukin-6-specific activation of the C/EBPδ gene in hepatocytes is mediated by Stat3 and Sp1
复制标题
DOI：
10.1128/mcb.18.4.2108
复制
发表时间：
1998-04-01
影响因子：
5.3
通讯作者：
Johnson, PF
中科院分区：
文献类型：
--
作者：
Cantwell, CA;Sterneck, E;Johnson, PF
C/EBP δ（CCAAT/增强子结合蛋白δ）被认为是肝细胞中急性期反应（APR）基因的调节因子。它的表达在肝细胞中显著增加，并且可以被白细胞介素-6（IL-6）诱导，白细胞介素-6是一种激活许多APR基因转录的急性时相介质。在这里，我们研究了肝癌细胞中IL-6调节C/EBP δ表达的机制，C/EBP δ启动子序列至~ 125 bp足以诱导报道基因的IL-6，并包括对PL-Ci反应性必需的apt APR元件（APRE），DNA结合实验和反式激活实验表明，Stat 3，但不是Stat 1，与此APRE相互作用。两个Spl位点，其中一个邻近APRE，是Ik-e诱导和Stat 3反式激活所必需的。因此，Stall和Spl协同作用以激活C/EBP δ启动子。用来自ICAM-1或C/EBP β启动子的Stat结合元件（SBE）替换APRE，两者都识别Stat 1和Stat 3，赋予对γ干扰素（一种选择性激活Stat 1的细胞因子）的响应性。序列比较表明，C/EBP δ和C/EBP β SBE的不同Stat结合特异性主要由单个碱基对差异决定。我们的研究结果表明，C/EBP δ基因表达的细胞因子特异性是由APRE序列。
C/EBP delta (CCAAT/enhancer binding protein delta) has been implicated as a regulator of acute-phase response (APR) genes in hepatocytes. Its expression increases dramatically in liver during the APR and can be induced in hepatic sell lines by interleukin-6 (IL-6), an acute-phase mediator that activates transcription of many APR genes, Here we have investigated the mechanism by which C/EBP delta expression is regulated by IL-6 in hepatoma cells, C/EBP delta promoter sequences to -125 bp are sufficient for IL-6 inducibility of a reporter gene and include apt APR element (APRE) that is essential for PL-Ci responsiveness, DNA binding experiments and transactivation assays demonstrate that Stat3, but mot Stat1, interacts with this APRE. Two Spl sites, one of which is adjacent to the APRE, are required for Ik-e induction and transactivation by Stat3. Thus, Stall and Spl function cooperatively to activate the C/EBP delta promoter. Replacement of the APRE with Stat binding elements (SBEs) from the ICAM-1 or C/EBP beta promoter, both of which recognize both Stat1 and Stat3, confers responsiveness to gamma interferon, a cytokine that selectively activates Stat1. Sequence comparisons suggest that the distinct Stat binding specificities of the C/EBP delta and C/EBP beta SBEs are determined primarily by a single base pair difference. Our findings indicate that the cytokine specificity of C/EBP delta gene expression is governed by the APRE sequence.