MicroRNA-124 Promotes Intestinal Inflammation by Targeting Aryl Hydrocarbon Receptor in Crohn’s Disease
MicroRNA-124 Promotes Intestinal Inflammation by Targeting Aryl Hydrocarbon Receptor in Crohn’s Disease
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MicroRNA-124 通过靶向克罗恩病中的芳基烃受体促进肠道炎症
DOI：
10.1093/ecco-jcc/jjw010
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发表时间：
2016
期刊：
影响因子：
--
通讯作者：
施瑞华
中科院分区：
文献类型：
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作者：
赵晔;施瑞华
摘要。背景与目的：微小RNA（miRNAs）的失调与多种疾病相关，包括克罗恩病（CD），但miRNAs的基本生物学功能和关键靶点在很大程度上仍不明确。本研究对活动期CD患者异常的结肠黏膜miRNAs进行了研究。
方法：通过实时定量聚合酶链反应检测活动期CD患者发炎结肠中的miRNA水平。在CD患者、肠上皮细胞（IECs）以及2,4,6 - 三硝基苯磺酸（TNBS）诱导的结肠炎小鼠中研究差异表达的miR - 124对其假定靶点芳香烃受体（AHR）的影响。通过在实验性结肠炎小鼠结肠内给予miR - 124抑制剂或前体，进一步研究miR - 124的作用。
结果：我们发现活动期CD患者结肠组织和IECs中miR - 124与AHR蛋白水平呈负相关。进一步的结果表明，miR - 124通过直接靶向Caco - 2细胞和HT - 29细胞中的AHR 3′ - 非翻译区（3′ - UTR）抑制AHR表达。miR - 124在体外通过对AHR的反向调节介导脂多糖刺激细胞的炎症反应。在TNBS诱导的结肠炎结肠中下调或上调miR - 124分别减轻或加重了实验性结肠炎。
结论：这些发现表明miR - 124通过抑制AHR诱导肠道炎症，调节促炎细胞因子的产生，从而促进CD的发病机制。
Abstract.Background and aims: Dysregulation of microRNAs (miRNAs) is associated with a variety of .diseases, including Crohn’s disease (CD), but the essential biological functions and crucial targets .of miRNAs remain largely unknown. The present study investigated the aberrant colonic mucosal .miRNAs in active CD patients..Methods: miRNA levels were assayed in inflamed colon of active CD patients by quantitative realtime polymerase chain reaction. The influence of differential expressed miR-124 on its putative .target, the aryl hydrocarbon receptor (AHR), was investigated in CD patients, intestinal epithelial .cells (IECs) and 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced colitis mice. The role of miR-.124 was further studied in experimental colitis mice by intracolonic administration of miR-124 .inhibitors or precursors..Results: We found an inverse correlation between miR-124 and AHR protein levels in colon .tissues and IECs of active CD patients. Further results demonstrated that miR-124 suppressed AHR .expression by directly targeting the AHR 3ʹ-untranslated region (3ʹ-UTR) in Caco-2 cells and HT-29 .cells. MiR-124 mediated the inflammatory response in lipopolysaccharide-stimulated cells through .retroregulation of AHR in vitro. Downregulation or upregulation of miR-124 in TNBS-induced colitic .colon alleviated or aggravated experimental colitis, respectively..Conclusions: These findings suggest that miR-124 induces intestinal inflammation by inhibiting AHR .to modulate pro-inflammatory cytokine production and thereby promotes the pathogenesis of CD.