Microbial pattern recognition causes distinct functional micro-RNA signatures in primary human monocytes.
Microbial pattern recognition causes distinct functional micro-RNA signatures in primary human monocytes.
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DOI：
10.1371/journal.pone.0031151
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Rosenstiel P
中科院分区：
文献类型：
--
作者：
Häsler R;Jacobs G;Till A;Grabe N;Cordes C;Nikolaus S;Lao K;Schreiber S;Rosenstiel P
微RNA（micro-RNAs，miRNAs）是一类短的非编码RNA，在转录后调节基因表达。一些研究已经证明了miRNA与广泛的细胞机制的相关性，然而，目前关于miRNA如何响应相关外部刺激（例如在疾病情况下）的知识非常有限。为了生成与炎症反应相关的miRNA网络的描述性图片，我们使用真实的时间PCR在原代人单核细胞中使用一组促炎组分如微生物模式分子（鞭毛蛋白、二酰化脂肽脂多糖、胞壁酰二肽）刺激、单核细胞增生李斯特菌感染和TNF-α作为促炎对照后定量330种miRNA的水平。因此，我们发现了不同的miRNA反应集群为每个刺激使用。此外，我们通过用相应的前体或抗-miRNA和微流控PCR阵列分离THP 1单核细胞，鉴定了三种选定的miRNA miR-129- 5 p、miR-146 a和miR-378的潜在靶基因，它们是PAMP特异性反应簇的一部分。miRNA诱导不同的转录组特征，例如，通过NOD 2-诱导子MDP选择性上调的miRNA 129 - 5 p的过表达，导致DEFB 1、IRAK 1、FBXW 7和IKK γ（Nemo）的上调。我们对高度共调节的miRNA簇的发现支持了miRNA在功能组中起作用的假设。这项研究表明，miRNAs在微调炎症机制中发挥着重要作用。对miRNA反应领域的进一步研究将有助于了解它们对基因表达的影响，并可能缩小炎症性疾病中mRNA和蛋白质表达之间的调控差距。
Micro-RNAs (miRNAs) are short, non-coding RNAs that regulate gene expression post transcriptionally. Several studies have demonstrated the relevance of miRNAs for a wide range of cellular mechanisms, however, the current knowledge on how miRNAs respond to relevant external stimuli, e.g. in disease scenarios is very limited. To generate a descriptive picture of the miRNA network associated to inflammatory responses, we quantified the levels of 330 miRNAs upon stimulation with a panel of pro-inflammatory components such as microbial pattern molecules (flagellin, diacylated lipopeptide lipopolysaccharide, muramyl dipeptide), infection with Listeria monocytogenes and TNF-α as pro-inflammatory control in primary human monocytes using real time PCR. As a result, we found distinct miRNA response clusters for each stimulus used. Additionally, we identified potential target genes of three selected miRNAs miR-129-5p, miR-146a and miR-378 which were part of PAMP-specific response clusters by transfecting THP1 monocytes with the corresponding pre- or anti-miRNAs and microfluidic PCR arrays. The miRNAs induced distinct transcriptomal signatures, e.g. overexpression of miRNA129-5p, which was selectively upregulated by the NOD2-elicitor MDP, led to an upregulation of DEFB1, IRAK1, FBXW7 and IKK γ (Nemo). Our findings on highly co-regulated clusters of miRNAs support the hypothesis that miRNAs act in functional groups. This study indicates that miRNAs play an important role in fine-tuning inflammatory mechanisms. Further investigation in the field of miRNA responses will help to understand their effects on gene expression and may close the regulatory gap between mRNA and protein expression in inflammatory diseases.