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首页> 外文期刊>American Journal of Physiology >Enhancer-dependent inhibition of mouse renin transcription by inflammatory cytokines.
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Enhancer-dependent inhibition of mouse renin transcription by inflammatory cytokines.

机译：炎症细胞因子对小鼠肾素转录的增强子依赖性抑制。

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Inflammatory cytokines have been shown to inhibit renin gene expression in the kidney in vivo and the kidney tumor-derived As4.1 cell line. In this report, we show that cytokines oncostatin M (OSM), IL-6, and IL-1beta inhibit transcriptional activity associated with 4.1 kb of the mouse renin 5'-flanking sequence in As4.1 cells. The 242-bp enhancer (-2866 to -2625 bp) is sufficient to mediate the observed inhibitory effects. Sequences within the enhancer required for inhibition by each of these cytokines have been determined by deletional and mutational analysis. Results indicate that a 39-bp region (CEC) containing a cAMP-responsive element, an E-box, and a steroid receptor-binding site, previously identified as the most critical elements for enhancer activity, is sufficient for the inhibition induced by IL-1beta. However, mutation of each of the three component sites does not abolish the inhibition by IL-1beta, suggesting that the target(s) of cytokine action may not be the transcription factors binding directly to these sites. This CEC region is also critical, but not sufficient, for the inhibition mediated by OSM and IL-6. These data suggest that the direct target of the associated cytokines may be coactivators interacting with transcription factors binding at the enhancer. Finally, we show that OSM treatment caused a 17-fold increase in promoter activity when only 2,625 bp of the Ren-1(c) flanking sequence were tested, in which the enhancer is not present. Three regions including -2625 to -1217 bp, the HOX.PBX binding site at -60 bp, and -59 to +6 bp have been found to contribute to this induction.
机译：炎症细胞因子已显示在体​​内和肾肿瘤衍生的As4.1细胞系中抑制肾素基因表达。在此报告中，我们显示了细胞因子抑制素M（OSM），IL-6和IL-1beta抑制与As4.1细胞中4.1 kb小鼠肾素5'侧翼序列相关的转录活性。 242-bp增强子（-2866至-2625 bp）足以介导观察到的抑制作用。已经通过缺失和突变分析确定了被这些细胞因子中的每一种抑制所需的增强子内的序列。结果表明，包含cAMP反应元件，E-box和类固醇受体结合位点的39 bp区域（CEC）先前被确定为增强子活性的最关键元件，足以抑制IL诱导-1beta。但是，三个成分位点每一个的突变都不会消除IL-1β的抑制作用，这表明细胞因子作用的靶点可能不是直接与这些位点结合的转录因子。对于由OSM和IL-6介导的抑制作用，该CEC区域也很关键，但并不足够。这些数据表明，相关细胞因子的直接靶标可能是与在增强子上结合的转录因子相互作用的共激活因子。最后，我们显示当仅测试2625 bp的Ren-1（c）侧翼序列时，OSM处理引起启动子活性增加17倍，其中不存在增强子。已发现包括-2625至-1217 bp，-60 bp处的HOX.PBX结合位点和-59至+6 bp的三个区域有助于该诱导。

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