Martinez-Nunez Rocio T, Bondanese Victor P, Louafi Fethi, Francisco-Garcia Ana S, Rupani Hitasha, Bedke Nicole, Holgate Stephen, Howarth Peter H, Davies Donna E, Sanchez-Elsner Tilman
Clinical and Experimental Sciences, Sir Henry Wellcome Laboratories, University of Southampton School of Medicine, Southampton General Hospital, Southampton, United Kingdom.
Clinical and Experimental Sciences, Sir Henry Wellcome Laboratories, University of Southampton School of Medicine, Southampton General Hospital, Southampton, United Kingdom; National Institute for Health Research (NIHR) Southampton Respiratory Biomedical Research Unit, Southampton Centre for Biomedical Research MP218, Southampton General Hospital, Southampton, United Kingdom.
PLoS One. 2014 Oct 31;9(10):e111659. doi: 10.1371/journal.pone.0111659. eCollection 2014.
MicroRNAs are short non-coding single stranded RNAs that regulate gene expression. While much is known about the effects of individual microRNAs, there is now growing evidence that they can work in co-operative networks. MicroRNAs are known to be dysregulated in many diseases and affect pathways involved in the pathology. We investigated dysregulation of microRNA networks using asthma as the disease model. Asthma is a chronic inflammatory disease of the airways characterized by bronchial hyperresponsiveness and airway remodelling. The airway epithelium is a major contributor to asthma pathology and has been shown to produce an excess of inflammatory and pro-remodelling cytokines such as TGF-β, IL-6 and IL-8 as well as deficient amounts of anti-viral interferons. After performing microRNA arrays, we found that microRNAs -18a, -27a, -128 and -155 are down-regulated in asthmatic bronchial epithelial cells, compared to cells from healthy donors. Interestingly, these microRNAs are predicted in silico to target several components of the TGF-β, IL-6, IL-8 and interferons pathways. Manipulation of the levels of individual microRNAs in bronchial epithelial cells did not have an effect on any of these pathways. Importantly, knock-down of the network of microRNAs miR-18a, -27a, -128 and -155 led to a significant increase of IL-8 and IL-6 expression. Interestingly, despite strong in silico predictions, down-regulation of the pool of microRNAs did not have an effect on the TGF-β and Interferon pathways. In conclusion, using both bioinformatics and experimental tools we found a highly relevant potential role for microRNA dysregulation in the control of IL-6 and IL-8 expression in asthma. Our results suggest that microRNAs may have different roles depending on the presence of other microRNAs. Thus, interpretation of in silico analysis of microRNA function should be confirmed experimentally in the relevant cellular context taking into account interactions with other microRNAs when studying disease.
微小RNA是一类短链非编码单链RNA，可调控基因表达。虽然我们对单个微小RNA的作用了解颇多，但现在越来越多的证据表明它们可以在协同网络中发挥作用。已知微小RNA在许多疾病中表达失调，并影响病理过程中涉及的信号通路。我们以哮喘作为疾病模型，研究了微小RNA网络的失调情况。哮喘是一种气道慢性炎症性疾病，其特征为支气管高反应性和气道重塑。气道上皮是哮喘病理过程的主要促成因素，已被证明会产生过量的炎症和促重塑细胞因子，如转化生长因子-β（TGF-β）、白细胞介素-6（IL-6）和白细胞介素-8（IL-8），同时抗病毒干扰素的产生量不足。在进行微小RNA阵列分析后，我们发现与健康供体的细胞相比，哮喘患者支气管上皮细胞中的微小RNA -18a、-27a、-128和-155表达下调。有趣的是，通过计算机模拟预测，这些微小RNA靶向TGF-β、IL-6、IL-8和干扰素信号通路的多个组分。在支气管上皮细胞中单独操纵单个微小RNA的水平对这些信号通路均无影响。重要的是，敲低微小RNA miR-18a、-27a、-128和-155的网络会导致IL-8和IL-6表达显著增加。有趣的是，尽管计算机模拟预测结果强烈，但微小RNA池的下调对TGF-β和干扰素信号通路并无影响。总之，通过生物信息学和实验工具，我们发现微小RNA失调在哮喘中对IL-6和IL-8表达的控制中具有高度相关的潜在作用。我们的结果表明，微小RNA的作用可能因其他微小RNA的存在而有所不同。因此，在研究疾病时，应在相关细胞环境中通过实验证实对微小RNA功能的计算机模拟分析结果，并考虑与其他微小RNA的相互作用。
