The signaling axis of microRNA-31/interleukin-25 regulates Th1/Th17-mediated inflammation response in colitis
The signaling axis of microRNA-31/interleukin-25 regulates Th1/Th17-mediated inflammation response in colitis
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microRNA-31/interleukin-25 的信号轴调节结肠炎中 Th1/Th17 介导的炎症反应。
DOI：
10.1038/mi.2016.102
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发表时间：
2017-07-01
影响因子：
8
通讯作者：
Chen, J.
中科院分区：
文献类型：
--
作者：
Shi, T.;Xie, Y.;Chen, J.
白细胞介素-25（IL-25）是一种重要的调节性细胞因子，在炎症反应中对黏膜免疫耐受起关键作用。然而，在克罗恩病（CD）中调节结肠IL-25表达的分子机制仍不清楚。在本研究中，证实了IL-25水平在2，4，6-三硝基苯磺酸（TNBS）诱导的结肠炎小鼠和IL-10敲除（KO）的自发性结肠炎小鼠中降低。在模型小鼠和CD患者的结肠中发现IL-25和miR-31之间呈负相关。此外，靶标验证分析表明，miR-31通过结合其信使RNA 3 '非翻译区直接调节IL-25的表达。改变结肠炎小鼠结肠组织中miR-31的水平可以影响黏膜IL-12/23介导的Th 1/Th 17通路，从而导致结肠炎症的减轻或加重。此外，抗miR-31在TNBS诱导的结肠炎中的治疗作用通过用IL-25抗体结肠治疗或结肠下调IL-25表达而消除。我们的研究结果表明IL-25可能是TNBS诱导的结肠炎中一种重要的抗炎细胞因子，miR-31靶向IL-25的信号转导可能是结肠炎症过程中IL-12/23介导的Th 1/Th 17炎症反应的调节机制。通过结肠内施用miR-31抑制剂恢复结肠IL-25表达并阻断Th 1/Th 17应答可能代表CD治疗的有希望的方法。
Interleukin-25 (IL-25) is an important regulatory cytokine that has a key role on mucosal immune tolerance during inflammation response. However, the molecular mechanism that regulates the colonic IL-25 expression in Crohn's disease (CD) remains unclear. In this study, IL-25 level was proved to decrease in 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis mice and IL-10 knockout (KO) spontaneous colitis mice. An inverse correlation between IL-25 and miR-31 was discovered in the colons from model mice and CD patients. Furthermore, target validation analysis demonstrated that miR-31 directly regulated IL-25 expression by binding to its messenger RNA 3'-untranslated region. Changing colonic miR-31 level in the colitis mice could affect the mucosal IL-12/23-mediated Th1/Th17 pathway and lead to either amelioration or aggravation of colonic inflammation. In addition, the therapeutic effects of anti-miR-31 in TNBS-induced colitis were abolished by colonic treatment with IL-25 antibody or colonic down-expression of IL-25. Our findings demonstrated that IL-25 could be a crucial anti-inflammatory cytokine in TNBS-induced colitis and the signaling of miR-31 targeting IL-25 might be a possible mechanism that regulates IL-12/23-mediated Th1/Th17 inflammatory responses during colonic inflammation process. Restoring colonic IL-25 expression and blocking Th1/Th17 responses via intracolonic administration of miR-31 inhibitor may represent a promising approach for CD treatment.