Roseburia intestinalis-derived flagellin is a negative regulator of intestinal inflammation
Roseburia intestinalis-derived flagellin is a negative regulator of intestinal inflammation
复制标题
肠罗斯氏菌衍生的鞭毛蛋白是肠道炎症的负调节因子
DOI：
10.1016/j.bbrc.2018.05.075
复制
发表时间：
2018-06-27
影响因子：
3.1
通讯作者：
Wang, Xiaoyan
中科院分区：
文献类型：
--
作者：
Quan, Yongsheng;Song, Kerui;Wang, Xiaoyan
本实验室前期研究表明，罗斯拜瑞氏菌Roseburia（R.在克罗恩病患者中，占主导地位的肠道细菌微生物群之一的大肠杆菌（大肠杆菌）显著减少，并保护结肠上皮细胞免受炎症损伤。然而，lncRNA在R.大肠杆菌鞭毛蛋白介导的抗炎作用仍不清楚。在这项研究中，我们研究了全球lncRNA表达谱，使用微阵列分析溃疡性结肠炎样本从DSS/鞭毛蛋白攻击的小鼠，并确定了鞭毛蛋白诱导上调lncRNA（HIF 1A-AS 2）。鞭毛蛋白通过激活p38-stat 1以剂量和时间依赖性方式诱导HIF 1A-AS 2表达。Stat 1和p38的选择性药理学抑制剂和这些基因的基因敲除消除了鞭毛蛋白诱导的HIF 1A-AS 2表达。荧光素酶报告基因检测结果表明，Flagellin通过增加stat 1的磷酸化激活HIF 1A-AS 2启动子。沉默HIF 1A-AS 2消除了鞭毛蛋白介导的抗炎作用，通过上调细胞因子表达进行评估，包括TNF-α，IL-1 β，IL-6和IL-12，但不是TNF β。此外，HIF 1A-AS 2的敲低显著增加了p65和JNK磷酸化，并充分消除了鞭毛蛋白介导的体内抗炎作用。我们的研究为lncRNA调节鞭毛蛋白介导的结肠炎症缓解机制提供了新的见解。这表明HIF 1A-AS 2可能是肠道炎症的调节剂，并代表了未来治疗的新靶点。(C)2018爱思唯尔公司All rights reserved.
Our previous study showed that the Roseburia intestinalis (R. intestinalis), one of the dominant intestinal bacterial microbiota, was significantly decreased in Crohn's disease patients and protected colon epithelial cells from inflammatory damage. However, the roles of lncRNAs in R. intestinalis flagellin-mediated anti-inflammation remain unclear. In this study, we investigate global lncRNA expression profiles using microarray analysis of ulcerative colitis samples from DSS/Flagellin-challenged mice and identified a Flagellin-induced upregulated lncRNA (HIF1A-AS2). Flagellin induced HIF1A-AS2 expression in a dose- and time-dependent manner via p38-stat1 activation. Selective pharmacological inhibitors of Stat1 and p38, and genetic knockdown of these genes abolished Flagellin-induced HIF1A-AS2 expression. In addition, luciferase reporter assay showed that Flagellin activated HIF1A-AS2 promotor via increasing stat1 phosphorylation. Silencing of HIF1A-AS2 abolished Flagellin-mediated anti-inflammatory effects, evaluating by upregulation of cytokines expression, including TNF-alpha, IL-1 beta, IL-6 and IL-12, but not TNF beta. In addition, knockdown of HIF1A-AS2 significantly increased p65 and Jnk phosphorylation, and sufficiently abolished Flagellin-mediated anti-inflammatory affects in vivo. Our study provides new insights into the mechanisms that lncRNAs regulate flagellin-mediated alleviation of colonic inflammation. It is indicated that HIF1A-AS2 may be a modulator of intestinal inflammation and represent a novel target for future therapeutics. (C) 2018 Elsevier Inc. All rights reserved.