Hes1 promotes the IL-22-mediated antimicrobial response by enhancing STAT3-dependent transcription in human intestinal epithelial cells
Hes1 promotes the IL-22-mediated antimicrobial response by enhancing STAT3-dependent transcription in human intestinal epithelial cells
复制标题
DOI：
10.1016/j.bbrc.2013.12.061
复制
发表时间：
2014-01-17
影响因子：
3.1
通讯作者：
Watanabe, Mamoru
中科院分区：
文献类型：
--
作者：
Murano, Tatsuro;Okamoto, Ryuichi;Watanabe, Mamoru
Notch 信号传导在肠上皮细胞 (IEC) 的增殖和分化中发挥着重要作用。我们之前已经表明，Notch 信号在溃疡性结肠炎 (UC) 发炎粘膜中上调，从而在组织再生中发挥不可或缺的作用。在这里，我们发现除了 Notch 信号传导之外，STAT3 信号传导在 UC 发炎的粘膜中也高度激活。 Notch 靶基因 Hes1 的强制表达显着增强了人类 IEC 中 IL-22 介导的 STAT3 依赖性转录。这种 STAT3 依赖性转录的增强是通过 Hes1 对 STAT3 的延长磷酸化来实现的。微阵列分析表明，Hes1 介导的 IL-22-STAT3 信号传导增强显着增加了人类 IEC 中编码抗菌肽（例如 REG1A、REG3A 和 REG3G）的基因的诱导。相反，用γ-分泌酶抑制剂降低Hes1蛋白水平会显着下调IEC中这些基因的诱导，导致对IL-22的反应明显较差。我们目前的研究结果确定了 Hes1 分子功能的新作用，其中该蛋白质可以与细胞因子信号相互作用并调节 IEC 的免疫反应。 (C) 2013 Elsevier Inc. 保留所有权利。
Notch signaling plays an essential role in the proliferation and differentiation of intestinal epithelial cells (IECs). We have previously shown that Notch signaling is up-regulated in the inflamed mucosa of ulcerative colitis (UC) and thereby plays an indispensable role in tissue regeneration. Here we show that in addition to Notch signaling, STAT3 signaling is highly activated in the inflamed mucosa of UC. Forced expression of the Notch target gene Hes1 dramatically enhanced the IL-22-mediated STAT3-dependent transcription in human IECs. This enhancement of STAT3-dependent transcription was achieved by the extended phosphorylation of STAT3 by Hes1. Microarray analysis revealed that Hes1 -mediated enhancement of IL-22-STAT3 signaling significantly increased the induction of genes encoding antimicrobial peptides, such as REG1A, REG3A and REG3G, in human IECs. Conversely, the reduction of Hes1 protein levels with a gamma-secretase inhibitor significantly down-regulated the induction of those genes in IECs, resulting in a markedly poor response to IL-22. Our present findings identify a new role for the molecular function of Hes1 in which the protein can interact with cytokine signals and regulate the immune response of IECs. (C) 2013 Elsevier Inc. All rights reserved.