Induction and regulatory function of miR-9 in human monocytes and neutrophils exposed to proinflammatory signals
Induction and regulatory function of miR-9 in human monocytes and neutrophils exposed to proinflammatory signals
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DOI：
10.1073/pnas.0810909106
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发表时间：
2009-03-31
影响因子：
11.1
通讯作者：
Locati, Massimo
中科院分区：
文献类型：
--
作者：
Bazzoni, Flavia;Rossato, Marzia;Locati, Massimo
炎症涉及一系列协调的、连续的和自限性的事件，这些事件由积极和消极的调节机制控制。最近的研究表明，microRNA（miRNAs），一种进化上保守的内源性22-核苷酸非编码RNA，通过在转录后水平抑制基因表达来调节炎症。在这项研究中，我们的特点是在人类中性粒细胞（PMN）和单核细胞的LIPS诱导的miRNA的档案。特别是，我们确定miR-9是TLR 4激活后两种细胞类型中唯一上调的miRNA（在365个分析的miRNA中）。miR-9也被TLR 2和TLR 7/8激动剂以及促炎细胞因子TNF-α和IL-1 β诱导，但不被IFN γ诱导。在人类中编码miR-9前体的3种不同基因中，我们表明LIPS以MyD 88和NF-κ B依赖的方式选择性地诱导位于CROC 4位点的miR-9-1的转录。在中性粒细胞和单核细胞中，LPS在转录和转录后水平调节NF KB 1，并且保守的miR-9种子维持NF KB 1转录的miR-9依赖性抑制。总之，这些数据表明，TLR 4激活的NF-κ B快速增加miR-9的表达，miR-9通过微调NF-κ B家族的关键成员的表达来操作NF-κ B依赖性应答的反馈控制。
Inflammation involves a coordinated, sequential, and self limiting sequence of events controlled by positive and negative regulatory mechanisms. Recent studies have shown that microRNAs (miRNAs), an evolutionarily conserved class of endogenous 22-nucleotide noncoding RNAs, contribute to the regulation of inflammation by repressing gene expression at the posttranscriptional level. In this study, we characterize the profile of miRNAs induced by LIPS in human polymorphonuclear neutrophils (PMN) and monocytes. In particular, we identify miR-9 as the only miRNA (among 365 analyzed) up-regulated in both cell types after TLR4 activation. miR-9 is also induced by TLR2 and TLR7/8 agonists and by the proinflammatory cytokines TNF-alpha and IL-1 beta, but not by IFN gamma. Among the 3 different genes encoding miR-9 precursors in humans, we show that LIPS selectively induces the transcription of miR-9-1 located in the CROC4 locus, in a MyD88- and NF-kappa B-dependent manner. In PMN and monocytes, LPS regulates NFKB1 at both the transcriptional and posttranscriptional levels, and a conserved miR-9 seed sustained a miR-9-dependent inhibition of the NFKB1 transcript. Overall, these data suggest that TLR4-activated NF-kappa B rapidly increases the expression of miR-9 that operates a feedback control of the NF-kappa B-dependent responses by fine tuning the expression of a key member of the NF-kappa B family.