State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
State Key Laboratory of Pharmaceutical Biotechnology, Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, China.
Gut. 2014 Aug;63(8):1247-57. doi: 10.1136/gutjnl-2012-304213. Epub 2013 Sep 2.
Emerging evidence suggests that microRNA (miRNA)-mediated gene regulation influences a variety of autoimmune disease processes, including Crohn's disease (CD), but the biological function of miRNAs in CD remains unclear. We examine miRNA level in colon tissues and study the potential functions of miRNAs that regulate pathological genes during the inflammation process.
miRNA levels were assayed in the inflamed colon of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced and IL-10 knockout (KO) chronic colitis mice and CD patients by microarray or qRT-PCR. The influence of differently expressed miR-141 on its putative target genes, CXCL12β, and leukocyte migration was investigated in colonic epithelia cells, colitis models and CD patients. The role of miR-141 was further studied in the experimental colitis mice by intracolonic administration of miR-141 precursors or inhibitors.
An inverse correlation between miR-141 and CXCL12β/total-CXCL12 was observed predominantly in the epithelial cells of the inflamed colons from colitic mice and CD patients. Further study demonstrated that miR-141 directly regulated CXCL12β expression and CXCL12β-mediated leukocyte migration. Upregulation or downregulation of miR-141 in the TNBS-induced or IL-10 KO colitic colon regulated leukocyte infiltration and alleviated or aggravated experimental colitis, respectively. Additionally, colonic overexpression of CXCL12β abolished the therapeutic effect of miR-141 in TNBS-induced colitis.
This study showed that the pathway of miR-141 targeting CXCL12β is a possible mechanism underlying inflammatory cell trafficking during colonic inflammation process. Inhibiting colonic CXCL12β expression and blocking colonic immune cell recruitment by using miRNA precursors represents a promising approach that may be valuable for CD treatment.
新出现的证据表明，微小 RNA（miRNA）介导的基因调控影响多种自身免疫性疾病过程，包括克罗恩病（CD），但 miRNA 在 CD 中的生物学功能仍不清楚。我们检查了结肠炎组织中的 miRNA 水平，并研究了在炎症过程中调节病理基因的 miRNA 的潜在功能。
通过微阵列或 qRT-PCR 分析 2,4,6-三硝基苯磺酸（TNBS）诱导和 IL-10 敲除（KO）慢性结肠炎小鼠和 CD 患者的结肠炎症组织中的 miRNA 水平。研究了在结肠上皮细胞、结肠炎模型和 CD 患者中，差异表达的 miR-141 对其假定靶基因 CXCL12β 和白细胞迁移的影响。通过结肠内给予 miR-141 前体或抑制剂进一步研究了 miR-141 在实验性结肠炎小鼠中的作用。
在结肠炎小鼠和 CD 患者的炎症结肠上皮细胞中观察到 miR-141 与 CXCL12β/总 CXCL12 呈负相关。进一步研究表明，miR-141 直接调节 CXCL12β 的表达和 CXCL12β 介导的白细胞迁移。TNBS 诱导或 IL-10 KO 结肠炎结肠中 miR-141 的上调或下调分别调节白细胞浸润并缓解或加重实验性结肠炎。此外，结肠过表达 CXCL12β 消除了 miR-141 在 TNBS 诱导的结肠炎中的治疗作用。
本研究表明，miR-141 靶向 CXCL12β 的途径可能是结肠炎症过程中炎症细胞迁移的潜在机制。通过使用 miRNA 前体抑制结肠 CXCL12β 的表达和阻断结肠免疫细胞募集可能是 CD 治疗的一种有前途的方法。
