NF-κB and STAT1 control CXCL1 and CXCL2 gene transcription
NF-κB and STAT1 control CXCL1 and CXCL2 gene transcription
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DOI：
10.1152/ajpendo.00347.2013
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发表时间：
2014-01-01
影响因子：
5.1
通讯作者：
Collier, J. Jason
中科院分区：
文献类型：
--
作者：
Burke, Susan J.;Lu, Danhong;Collier, J. Jason
糖尿病是由免疫细胞侵入朗格汉斯胰岛引起的，最终导致产生胰岛素的β细胞的选择性破坏。这个过程是如何开始的还不是很清楚。在这项研究中，我们研究了CXCL1和CXCL2基因的调控，它们编码促进CXCR2（+）细胞（如中性粒细胞）向分泌组织迁移的蛋白质。在此，我们发现IL-1 β显著增强了大鼠胰岛和β细胞系中CXCL1和CXCL2基因的表达，从而导致这些蛋白的分泌增加。CXCL1和CXCL2还能刺激人中性粒细胞表面特异性整合素蛋白的表达。两个基因启动子中一致存在的NF-kappa B基因组序列突变降低了IL-1 β促进转录的能力。此外，IL-1 β诱导NF-kappa B的p65和p50亚基与这些共识的kappa B调控元件以及位于每个基因核心启动子区域附近的其他kappa B位点结合。此外，丝氨酸磷酸化的STAT1结合到CXCL1和CXCL2基因的启动子上。我们进一步发现，IL-1 β在转录因子结合和转录物积累的时间框架内诱导组蛋白H3的特异性翻译后修饰。我们得出结论，IL-1 β介导的胰腺β细胞中CXCL1和CXCL2基因的调控需要刺激诱导组蛋白化学修饰的改变，nf - κ B和STAT1转录因子在近端基因启动子内的基因组调控序列的募集，以及RNA聚合酶II磷酸化形式的增加。
Diabetes mellitus results from immune cell invasion into pancreatic islets of Langerhans, eventually leading to selective destruction of the insulin-producing beta-cells. How this process is initiated is not well understood. In this study, we investigated the regulation of the CXCL1 and CXCL2 genes, which encode proteins that promote migration of CXCR2(+) cells, such as neutrophils, toward secreting tissue. Herein, we found that IL-1 beta markedly enhanced the expression of the CXCL1 and CXCL2 genes in rat islets and beta-cell lines, which resulted in increased secretion of each of these proteins. CXCL1 and CXCL2 also stimulated the expression of specific integrin proteins on the surface of human neutrophils. Mutation of a consensus NF-kappa B genomic sequence present in both gene promoters reduced the ability of IL-1 beta to promote transcription. In addition, IL-1 beta induced binding of the p65 and p50 subunits of NF-kappa B to these consensus kappa B regulatory elements as well as to additional kappa B sites located near the core promoter regions of each gene. Additionally, serine-phosphorylated STAT1 bound to the promoters of the CXCL1 and CXCL2 genes. We further found that IL-1 beta induced specific posttranslational modifications to histone H3 in a time frame congruent with transcription factor binding and transcript accumulation. We conclude that IL-1 beta-mediated regulation of the CXCL1 and CXCL2 genes in pancreatic beta-cells requires stimulus-induced changes in histone chemical modifications, recruitment of the NF-kappa B and STAT1 transcription factors to genomic regulatory sequences within the proximal gene promoters, and increases in phosphorylated forms of RNA polymerase II.