Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Beaumont Hospital, Ireland.
J Immunol. 2010 Feb 15;184(4):1702-9. doi: 10.4049/jimmunol.0902669. Epub 2010 Jan 18.
Cystic fibrosis (CF) is one of the most common lethal genetic diseases in which the role of microRNAs has yet to be explored. Predicted to be regulated by miR-126, TOM1 (target of Myb1) has been shown to interact with Toll-interacting protein, forming a complex to regulate endosomal trafficking of ubiquitinated proteins. TOM1 has also been proposed as a negative regulator of IL-1beta and TNF-alpha-induced signaling pathways. MiR-126 is highly expressed in the lung, and we now show for the first time differential expression of miR-126 in CF versus non-CF airway epithelial cells both in vitro and in vivo. MiR-126 downregulation in CF bronchial epithelial cells correlated with a significant upregulation of TOM1 mRNA, both in vitro and in vivo when compared with their non-CF counterparts. Introduction of synthetic pre-miR-126 inhibited luciferase activity in a reporter system containing the full length 3'-untranslated region of TOM1 and resulted in decreased TOM1 protein production in CF bronchial epithelial cells. Following stimulation with LPS or IL-1beta, overexpression of TOM1 was found to downregulate NF-kappaB luciferase activity. Conversely, TOM1 knockdown resulted in a significant increase in NF-kappaB regulated IL-8 secretion. These data show that miR-126 is differentially regulated in CF versus non-CF airway epithelial cells and that TOM1 is a miR-126 target that may have an important role in regulating innate immune responses in the CF lung. To our knowledge, this study is the first to report of a role for TOM1 in the TLR2/4 signaling pathways and the first to describe microRNA involvement in CF.
囊性纤维化（CF）是最常见的致命性遗传疾病之一，其 microRNA 的作用尚未得到探索。TOM1（Myb1 的靶标）被预测受 miR-126 调控，已显示与 Toll 相互作用蛋白相互作用，形成复合物以调节泛素化蛋白的内体运输。TOM1 也被提出作为 IL-1β和 TNF-α诱导的信号通路的负调节剂。miR-126 在肺部高表达，我们现在首次显示 miR-126 在 CF 与非 CF 气道上皮细胞中的差异表达，无论是在体外还是体内。CF 支气管上皮细胞中 miR-126 的下调与 TOM1 mRNA 的显著上调相关，与非 CF 对照相比，无论是在体外还是体内均如此。在含有全长 3'-非翻译区的报告系统中引入合成 pre-miR-126 抑制了荧光素酶活性，并导致 CF 支气管上皮细胞中 TOM1 蛋白的产生减少。在用 LPS 或 IL-1β刺激后，发现 TOM1 的过表达会下调 NF-κB 荧光素酶活性。相反，TOM1 的敲低导致 NF-κB 调节的 IL-8 分泌显著增加。这些数据表明，miR-126 在 CF 与非 CF 气道上皮细胞中的差异表达，并且 TOM1 是 miR-126 的靶标，在 CF 肺中可能对调节先天免疫反应具有重要作用。据我们所知，这项研究首次报道了 TOM1 在 TLR2/4 信号通路中的作用，并且首次描述了 microRNA 参与 CF。
