MiR-155 modulates the inflammatory phenotype of intestinal myofibroblasts by targeting SOCS1 in ulcerative colitis.
MiR-155 modulates the inflammatory phenotype of intestinal myofibroblasts by targeting SOCS1 in ulcerative colitis.
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DOI：
10.1038/emm.2015.21
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发表时间：
2015-05-22
影响因子：
12.8
通讯作者：
Castagliuolo, Ignazio
中科院分区：
文献类型：
--
作者：
Pathak, Surajit;Grillo, Alessia Rosaria;Scarpa, Melania;Brun, Paola;D'Inca, Renata;Nai, Laura;Banerjee, Antara;Cavallo, Donatella;Barzon, Luisa;Palu, Giorgio;Sturniolo, Giacomo Carlo;Buda, Andrea;Castagliuolo, Ignazio
调节炎症和免疫反应的microRNA（miR）-155水平异常已在炎症性肠病（IBD）患者的结肠粘膜中得到证实，尽管其在疾病病理生理学中的作用尚不清楚。我们研究了miR-155在肠肌成纤维细胞（IMF）获得和维持活化表型中的作用，IMF是IBD中导致粘膜损伤的关键细胞群。从健康对照、溃疡性结肠炎（UC）和克罗恩病（CD）患者的结肠活检中分离IMF。在基础条件下和暴露于TNF-α、白细胞介素（IL）-1β、脂多糖（LPS）或TGF-β1后，通过定量逆转录-PCR定量IMF中的miR-155。分别通过酶联免疫吸附试验和western blot评估miR-155模拟物或抑制剂转染对细胞因子释放和细胞因子信号转导抑制因子1（SOCS 1）表达的影响。使用荧光素酶报告基因构建体评估miR-155对靶基因SOCS 1表达的调节。我们发现miR-155在UC中显著上调，与对照和CD衍生的IMF相比。此外，TNF-α和LPS可显著增加IMF中miR-155的表达，而TGF-β1和IL-1β则无此作用。对照IMF中miR-155的异位表达增加了细胞因子的释放，而它下调了SOCS 1的表达。UC-IMF中的MiR-155敲低减少了细胞因子的产生并增强了SOCS 1的表达。荧光素酶报告基因分析表明miR-155直接靶向SOCS 1。此外，在对照IMF中沉默SOCS 1显著增加IL-6和IL-8的释放。总之，我们的数据表明炎症介质诱导UC患者IMF中miR-155的表达。miR-155通过下调SOCS 1的表达而改变IMF的炎症表型。
Abnormal levels of microRNA (miR)-155, which regulate inflammation and immune responses, have been demonstrated in the colonic mucosa of patients with inflammatory bowel diseases (IBD), although its role in disease pathophysiology is unknown. We investigated the role of miR-155 in the acquisition and maintenance of an activated phenotype by intestinal myofibroblasts (IMF), a key cell population contributing to mucosal damage in IBD. IMF were isolated from colonic biopsies of healthy controls, ulcerative colitis (UC) and Crohn's disease (CD) patients. MiR-155 in IMF was quantified by quantitative reverse transcription-PCR in basal condition and following exposure to TNF-α, interleukin (IL)-1β, lipopolysaccharide (LPS) or TGF-β1. The effects of miR-155 mimic or inhibitor transfection on cytokine release and suppressor of cytokine signaling 1 (SOCS1) expression were assessed by enzyme-linked immunosorbent assay and western blot, respectively. Regulation of the target gene SOCS1 expression by miR-155 was assessed using luciferase reporter construct. We found that miR-155 was significantly upregulated in UC as compared with control- and CD-derived IMF. Moreover, TNF-α and LPS, but not TGF-β1 and IL-1β, significantly increased miR-155 expression in IMF. Ectopic expression of miR-155 in control IMF augmented cytokines release, whereas it downregulated SOCS1 expression. MiR-155 knockdown in UC-IMF reduced cytokine production and enhanced SOCS1 expression. Luciferase reporter assay demonstrated that miR-155 directly targets SOCS1. Moreover, silencing of SOCS1 in control IMF significantly increased IL-6 and IL-8 release. In all, our data suggest that inflammatory mediators induce miR-155 expression in IMF of patients with UC. By downregulating the expression of SOCS1, miR-155 wires IMF inflammatory phenotype.
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