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首页> 外文期刊>American Journal of Physiology >Regulation of NF-kappaB responses by epigenetic suppression of IkappaBalpha expression in HCT116 intestinal epithelial cells.
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Regulation of NF-kappaB responses by epigenetic suppression of IkappaBalpha expression in HCT116 intestinal epithelial cells.

机译：通过表观遗传抑制HCT116肠上皮细胞中IkappaBalpha表达来调节NF-kappaB反应。

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摘要

Intestinal epithelial cells play critical roles in regulating mucosal immunity. Since epigenetic factors such as DNA methylation and histone modifications are implicated in aging, carcinogenesis, and immunity, we set out to assess any role for epigenetic factors in the regulation of intestinal epithelial cell immune responses. Experiments were conducted using the HCT116 cell line, and a subclone was genetically engineered to lack DNA methyltransferases (DNMT). The induction of the chemokine interleukin-8 and the antiapoptotic protein cFLIP by tumor necrosis factor-alpha were markedly less in HCT116 cells lacking DNMT than in parental cells. These effects were accompanied by lower monocyte chemotaxis and higher caspase signaling in HCT116 cells lacking DNMT than parental cells. Tumor necrosis factor-alpha-induced NF-kappaB activation was blocked and IkappaBalpha expression was higher in HCT116 cells lacking DNMT than in parental cells. A CpG island in the IkappaBalpha gene promoter region was found to contain variable levels of methylation in parental HCT116 cells. Chromatin immunoprecipitation analysis of histone proteins bound to the IkappaBalpha gene promoter revealed that higher levels of IkappaBalpha expression in HCT116 cells lacking DNMT compared with parental cells were accompanied by more chromatin marks permissive to gene transcription. These findings show that epigenetic factors influence the NF-kappaB system in intestinal epithelial cells, resulting in a previously unrecognized mechanism of innate immune regulation.
机译：肠上皮细胞在调节粘膜免疫中起关键作用。由于表观遗传因素（例如DNA甲基化和组蛋白修饰）与衰老，致癌作用和免疫力有关，因此我们着手评估表观遗传因素在肠道上皮细胞免疫反应调节中的作用。使用HCT116细胞系进行了实验，并对亚克隆进行了基因工程改造，使其缺乏DNA甲基转移酶（DNMT）。在缺乏DNMT的HCT116细胞中，由肿瘤坏死因子-α诱导的趋化因子白介素8和抗凋亡蛋白cFLIP明显低于亲代细胞。在缺乏DNMT的HCT116细胞中，这些效应伴随着较低的单核细胞趋化性和较高的半胱天冬酶信号转导，而其亲代细胞却没有。缺乏DNMT的HCT116细胞中肿瘤坏死因子-α诱导的NF-κB活化被阻断，IkappaBα表达高于亲代细胞。 IkappaBalpha基因启动子区域中的一个CpG岛被发现在亲本HCT116细胞中含有可变水平的甲基化。与IkappaBalpha基因启动子结合的组蛋白的染色质免疫沉淀分析显示，与亲代细胞相比，缺少DNMT的HCT116细胞中IkappaBalpha表达水平更高，同时伴随有更多的染色质标记允许基因转录。这些发现表明，表观遗传因素影响肠上皮细胞中的NF-κB系统，从而导致了先天免疫调节的未知机制。

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