Opposite effects of miR-155 in the initial and later stages of lipopolysaccharide (LPS)-induced inflammatory response
Opposite effects of miR-155 in the initial and later stages of lipopolysaccharide (LPS)-induced inflammatory response
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miR-155 在脂多糖 (LPS) 诱导的炎症反应的初始和后期阶段具有相反的作用
DOI：
10.1631/jzus.b2000826
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发表时间：
2021-07-01
影响因子：
5.1
通讯作者：
Jin, Hongchuan
中科院分区：
文献类型：
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作者：
Liu, Yuhua;Wan, Xiaopeng;Jin, Hongchuan
虽然microRNA-155(miR-155)被认为是一种促炎介质，但累积的证据表明，它在巨噬细胞和树突状细胞中也具有抗炎作用。在这项研究中，我们发现在脂多糖刺激下，超过一半的潜在miR-155靶向基因的表达发生了戏剧性的变化，223个基因下调，85个基因上调，其中包括细胞因子信号转导抑制因子1(SOCS1)和转化生长因子激活的蛋白1结合蛋白2(TAB2)，这两个基因参与了miR-155介导的Toll样受体4(TLR4)信号通路的调节。我们还发现，miR-155在内毒素诱导的炎症反应的早期主要通过抑制TAB2蛋白的翻译发挥抗炎介质的作用，在后期通过下调SOCS1作为促炎介质。同时，巨噬细胞中TAB2 3‘非翻译区的过度表达通过与miR-155的竞争结合促进了内毒素耐受的发生，从而导致SOCS1蛋白表达水平升高。这些发现为理解微调内毒素诱导的先天性免疫反应的调节机制提供了新的见解。
Although microRNA-155 (miR-155) is considered a pro-inflammatory mediator, cumulative evidence indicates that it also has anti-inflammatory effects in macrophages and dendritic cells. In this study, we identified the dramatic expression changes of more than half of potential miR-155-targeted genes upon lipopolysaccharide (LPS) stimulation; 223 genes were down-regulated and 85 genes were up-regulated, including suppressor of cytokine signaling 1 (SOCS1) and transforming growth factor-β-activated kinase 1-binding protein 2 (TAB2), two well-known genes involved in miR-155-mediated regulation of the Toll-like receptor 4 (TLR4) signaling pathway. We also found that miR-155 acted as an anti-inflammatory mediator in the initial stage of LPS-induced inflammatory response mainly through repressing TAB2 protein translation, and as a pro-inflammatory mediator by down-regulating SOCS1 in the later stage. Meanwhile, overexpression of TAB2 3′ untranslated region (UTR) in macrophages promoted the development of endotoxin tolerance by competing for binding with miR-155, which resulted in an elevated expression level of SOCS1 protein. These findings provide new insights for understanding the regulatory mechanisms in fine-tuning of LPS-induced innate immune response.