miR-301a promotes intestinal mucosal inflammation through induction of IL-17A and TNF-α in IBD
miR-301a promotes intestinal mucosal inflammation through induction of IL-17A and TNF-α in IBD
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miR-301a 通过诱导 IBD 中的 IL-17A 和 TNF-α 促进肠粘膜炎症
DOI：
10.1136/gutjnl-2015-309389
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发表时间：
2016-12-01
期刊：
影响因子：
24.5
通讯作者：
Liu, Zhanju
中科院分区：
文献类型：
--
作者：
He, Chong;Shi, Yan;Liu, Zhanju
目的miR-301 a参与多种自身免疫性疾病的发生和发展，但miR-301 a是否参与IBD的发病机制尚不清楚。方法采用实时荧光定量PCR技术检测IBD患者外周血单个核细胞（PBMC）和炎症黏膜中miR-301 a的表达。用慢病毒编码的前体miR-301 a（LV-miR-301 a）或miR-301 a的反向互补序列（LV-anti-miR-301 a）转导外周血CD 4 + T细胞，并在体外研究其分化和活化。结果与健康对照组相比，IBD患者PBMC和炎症黏膜中miR-301 a表达显著上调，炎症黏膜中miR-301 a表达显著上调，炎症黏膜中miR-301 a表达显著上调，炎症黏膜中miR-301 a表达显著上调。用肿瘤坏死因子-α（TNF-α）刺激显著增强IBD CD 4 + T细胞中的miR-301 a表达，这被抗TNF-α mAb（英夫利昔单抗）治疗显著逆转。与表达LV-抗-miR-301 a的细胞相比，LV-miR-301 a转导入IBD患者的CD 4 + T细胞促进了Th 17细胞分化和TNF-α的产生。SNIP 1作为miR-301 a的功能性靶点在miR-301 a表达中降低，但在LV-抗-miR-301 a表达中增加。敲低SNIP 1可增强Th 17细胞的分化。此外，在TNBS诱导的小鼠结肠炎模型中，结肠内施用反义miR-301 a显著降低了白细胞介素（IL）-17A（+）细胞的数量和促炎细胞因子的量（例如，IL-17 A，结论我们的数据揭示了一种新的机制，在这种机制中，301 a在PBMC和IBD炎症粘膜中通过下调SNIP 1促进Th 17细胞分化。体内阻断miR-301 a可能成为IBD治疗的一种新方法。
Objective MicroRNA (miR)-301a is known to be involved in the tumourigenesis and pathogenesis of several autoimmune diseases, but it remains unclear whether miR-301a is associated with the pathogenesis of IBD.Methods miR-301a expression was assessed in peripheral blood mononuclear cells (PBMC) and inflamed mucosa of patients with IBD by quantitative real-time-PCR. Peripheral blood CD4+ T cells were transduced with lentivirus-encoding pre-miR-301a (LV-miR-301a) or a reverse complementary sequence of miR-301a (LV-anti-miR-301a), and their differentiation and activation were investigated in vitro. Antisense miR-301a was administered into mice during trinitrobenzene sulphonic acid (TNBS)-induced colitis to determine its role in colitis.Results miR-301a expression was significantly upregulated in PBMC and inflamed mucosa of patients with IBD compared with healthy controls. Stimulation with tumour necrosis factor-alpha (TNF-alpha) significantly enhanced miR-301a expression in IBD CD4+ T cells, which was markedly reversed by anti-TNF-alpha mAb (Infliximab) treatment. Transduction of LV-miR-301a into CD4+ T cells from patients with IBD promoted the Th17 cell differentiation and TNF-alpha production compared with the cells with expression of LV-anti-miR-301a. SNIP1 as a functional target of miR-301a was reduced in miR-301a expression but increased in LV-anti-miR-301a expression. Knockdown of SNIP1 could enhance Th17 cell differentiation. Furthermore, intracolonical administration of antisense miR-301a in TNBS-induced mouse colitis model significantly decreased numbers of interleukin (IL)-17A(+) cells and amounts of pro-inflammatory cytokines (eg, IL-17A, TNF-alpha) in inflamed colon.Conclusions Our data reveal a novel mechanism in which the elevated miR-301a in PBMC and inflamed mucosa of IBD promotes Th17 cell differentiation through downregulation of SNIP1. Blockade of miR-301a in vivo may serve as a novel therapeutic approach in the treatment of IBD.