Post-Transcriptional Regulation of Cystic Fibrosis Transmembrane Conductance Regulator Expression and Function by MicroRNAs
Post-Transcriptional Regulation of Cystic Fibrosis Transmembrane Conductance Regulator Expression and Function by MicroRNAs
复制标题
DOI：
10.1165/rcmb.2012-0430oc
复制
发表时间：
2013-10-01
影响因子：
6.4
通讯作者：
McCray, Paul B., Jr.
中科院分区：
文献类型：
--
作者：
Ramachandran, Shyam;Karp, Philip H.;McCray, Paul B., Jr.
MicroRNAs （miRNAs）越来越被认为是基因表达的重要转录后调节因子，其行为的变化可能导致疾病状态。在正常或病变情况下，关于miRNA在气道上皮中的功能知之甚少。我们分析了miRNA在人囊性纤维化（CF）和非CF气道上皮的高分化原代培养中的表达，发现miR-509-3p和miR-494浓度在CF上皮中升高。转染miR-509-3p或miR-494模拟物的人非cf气道上皮显示囊性纤维化跨膜传导调节因子（CFTR）表达降低，而其各自的抗mir则发挥相反的作用。有趣的是，这两种mirna协同调节CFTR的表达。用金黄色葡萄球菌感染非cf气道上皮细胞，或用促炎细胞因子tnf - α或IL-1 β刺激非cf气道上皮细胞，我们观察到mirna表达增加，CFTR表达和功能同时降低，提示炎症介质可能调节这些mirna。用miR-509-3p和miR-494的抗mirna转染上皮，或在用TNF α或IL-1 β刺激细胞之前抑制NF-kappa B信号传导，抑制了这些反应，表明这两种mirna的表达对NF-kappa B信号传导有反应。因此，miR-509-3p和miR-494是正常非cf气道上皮中CFTR丰度和功能的动态调节因子。
MicroRNAs (miRNAs) are increasingly recognized as important posttranscriptional regulators of gene expression, and changes in their actions can contribute to disease states. Little is understood regarding miRNA functions in the airway epithelium under normal or diseased conditions. We profiled miRNA expression in well-differentiated primary cultures of human cystic fibrosis (CF) and non-CF airway epithelia, and discovered that miR-509-3p and miR-494 concentrations were increased in CF epithelia. Human non-CF airway epithelia, transfected with the mimics of miR-509-3p or miR-494, showed decreased cystic fibrosis transmembrane conductance regulator (CFTR) expression, whereas their respective anti-miRs exerted the opposite effect. Interestingly, the two miRNAs acted cooperatively in regulating CFTR expression. Upon infecting non-CF airway epithelial cells with Staphylococcus aureus, or upon stimulating them with the proinflammatory cytokines TNF-alpha or IL-1 beta, we observed an increased expression of both miRNAs and a concurrent decrease in CFTR expression and function, suggesting that inflammatory mediators may regulate these miRNAs. Transfecting epithelia with anti-miRs for miR-509-3p and miR-494, or inhibiting NF-kappa B signaling before stimulating cells with TNF alpha or IL-1 beta, suppressed these responses, suggesting that the expression of both miRNAs was responsive to NF-kappa B signaling. Thus, miR-509-3p and miR-494 are dynamic regulators of CFTR abundance and function in normal, non-CF airway epithelia.