Dang Xiaomin, He Beibei, Ning Qian, Liu Ya, Chang Ying, Chen Mingwei
Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China.
Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China.
Int Immunopharmacol. 2020 Jun;83:106475. doi: 10.1016/j.intimp.2020.106475. Epub 2020 Apr 10.
MicroRNAs (miRNAs) have emerged as critical modulators involved in the regulation of airway remodeling in asthma. MicroRNA-182-5p (miR-182-5p) has been reported as a key miRNA in regulating the proliferation and migration of various cell types, and its dysfunction contributes is implicated in a wide range of pathological processes. Yet, it remains unknown whether miR-182-5p modulates the proliferation and migration of airway smooth muscle (ASM) cells during asthma. In the present study, we aimed to determine the potential role of miR-182-5p in regulating the proliferation and migration of ASM cells induced by tumor necrosis factor (TNF)-α in vitro. We found that TNF-α stimulation markedly reduced miR-182-5p expression in ASM cells. Gain-of-function experiments showed that miR-182-5p upregulation suppressed the proliferation and migration of ASM cells induced by TNF-α. By contrast, miR-182-5p inhibition had the opposite effect. Notably, tripartite motif 8 (TRIM8) was identified as a target gene of miR-182-5p. TRIM8 expression was induced by TNF-α stimulation, and TRIM8 knockdown markedly impeded TNF-α-induced ASM cell proliferation and migration. Moreover, miR-182-5p overexpression or TRIM8 knockdown significantly downregulated the activation of nuclear factor-κB (NF-κB) induced by TNF-α. However, TRIM8 restoration partially reversed the miR-182-5p-mediated inhibitory effect on TNF-α-induced ASM cell proliferation and migration. In conclusion, our study indicates that miR-182-5p restricts TNF-α-induced ASM cell proliferation and migration through downregulation of NF-κB activation via targeting TRIM8. The results of our study highlight the potential importance of the miR-182-5p/TRIM8/NF-κB axis in the airway remodeling of asthma.
微小RNA（miRNA）已成为参与哮喘气道重塑调节的关键调节因子。据报道，微小RNA-182-5p（miR-182-5p）是调节多种细胞类型增殖和迁移的关键miRNA，其功能障碍与多种病理过程有关。然而，miR-182-5p是否在哮喘期间调节气道平滑肌（ASM）细胞的增殖和迁移仍不清楚。在本研究中，我们旨在确定miR-182-5p在体外调节肿瘤坏死因子（TNF）-α诱导的ASM细胞增殖和迁移中的潜在作用。我们发现TNF-α刺激显著降低了ASM细胞中miR-182-5p的表达。功能获得实验表明，miR-182-5p上调抑制了TNF-α诱导的ASM细胞的增殖和迁移。相比之下，miR-182-5p抑制则产生相反的效果。值得注意的是，三联基序8（TRIM8）被鉴定为miR-182-5p的靶基因。TRIM8表达由TNF-α刺激诱导，TRIM8敲低显著阻碍了TNF-α诱导的ASM细胞增殖和迁移。此外，miR-182-5p过表达或TRIM8敲低显著下调了TNF-α诱导的核因子-κB（NF-κB）的激活。然而，TRIM8恢复部分逆转了miR-182-5p介导的对TNF-α诱导的ASM细胞增殖和迁移的抑制作用。总之，我们的研究表明，miR-182-5p通过靶向TRIM8下调NF-κB激活来限制TNF-α诱导的ASM细胞增殖和迁移。我们的研究结果突出了miR-182-5p/TRIM8/NF-κB轴在哮喘气道重塑中的潜在重要性。
