Induction of microRNA-155 is TLR- and type IV secretion system-dependent in macrophages and inhibits DNA-damage induced apoptosis
Induction of microRNA-155 is TLR- and type IV secretion system-dependent in macrophages and inhibits DNA-damage induced apoptosis
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DOI：
10.1073/pnas.1116125109
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发表时间：
2012-05-08
影响因子：
11.1
通讯作者：
Meyer, Thomas F.
中科院分区：
文献类型：
--
作者：
Koch, Manuel;Mollenkopf, Hans-Joachim;Meyer, Thomas F.
幽门螺杆菌是一种胃病原体，在世界范围内造成很高的疾病负担。炎症反应失调，可能涉及巨噬细胞，与H。幽门螺杆菌诱导的病理学，和microRNA，如miR-155，最近出现的先天免疫和炎症反应的关键调节因子。miR-155在单核细胞衍生的细胞中受Toll样受体（TLR）配体调节，并且已显示在H.幽门感染在此，我们研究了H. pylori感染，并使用微阵列分析检测该microRNA的下游mRNA靶。我们报告了miR-155的TLR 2/4和NOD 1/2非依赖性上调，发现其依赖于主要的H。pylori致病性决定簇，IV型分泌系统（T4 SS）。miR-155的表达依赖于NF-κ B信号传导，但不依赖于CagA。微阵列分析确定了miR-155在人乳腺癌中的已知基因靶点。pylori感染是促凋亡的。我们还鉴定并验证了靶点Tspan 14、Lpin 1和Pmaip 1的3'UTR中的miR-155结合位点。我们观察到H. pylori感染的miR-155（-/-）Bp 53比野生型Bp 53对顺铂DNA损伤诱导的细胞凋亡更敏感。因此，我们的数据表明了原型H的函数。pylori致病因子T4 SS在Bcirrhosis中上调miR-155。我们认为miR-155的抗凋亡作用可以增强巨噬细胞对H.幽门感染
Helicobacter pylori is a gastric pathogen responsible for a high disease burden worldwide. Deregulated inflammatory responses, possibly involving macrophages, are implicated in H. pylori-induced pathology, and microRNAs, such as miR-155, have recently emerged as crucial regulators of innate immunity and inflammatory responses. miR-155 is regulated by Toll-like receptor (TLR) ligands in monocyte-derived cells and has been shown to be induced in macrophages during H. pylori infection. Here, we investigated the regulation of miR-155 expression in primary murine bone marrow-derived macrophages (BMMs) during H. pylori infection and examined the downstream mRNA targets of this microRNA using microarray analysis. We report TLR2/4- and NOD1/2-independent up-regulation of miR-155, which was found to be dependent on the major H. pylori pathogenicity determinant, the type IV secretion system (T4SS). miR-155 expression was dependent on NF-kappa B signaling but was independent of CagA. Microarray analysis identified known gene targets of miR-155 in BMMs during H. pylori infection that are proapoptotic. We also identified and validated miR-155 binding sites in the 3' UTRs of the targets, Tspan14, Lpin1, and Pmaip1. We observed that H. pylori-infected miR-155(-/-) BMMs were significantly more susceptible to cisplatin DNA damage-induced apoptosis than were wild-type BMMs. Thus, our data suggest a function for the prototypical H. pylori pathogenicity factor, the T4SS, in the up-regulation of miR-155 in BMMs. We propose the antiapoptotic effects of miR-155 could enhance macrophage resistance to apoptosis induced by DNA damage during H. pylori infection.