IL-1 Receptor Regulates microRNA-135b Expression in a Negative Feedback Mechanism during Cigarette Smoke-Induced Inflammation
IL-1 Receptor Regulates microRNA-135b Expression in a Negative Feedback Mechanism during Cigarette Smoke-Induced Inflammation
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DOI：
10.4049/jimmunol.1202456
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发表时间：
2013-04-01
影响因子：
4.4
通讯作者：
Stampfli, Martin
中科院分区：
文献类型：
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作者：
Halappanavar, Sabina;Nikota, Jake;Stampfli, Martin
尽管已知microRNA-135 b（miR-135 b）与癌症相关，但最近的研究表明，它在用纳米颗粒激发的小鼠的肺组织中被大量诱导，这表明这种microRNA在介导炎症反应中起着关键作用。在这项研究中，我们研究了暴露于香烟烟雾或不可分型流感嗜血杆菌（NTHi）的小鼠中miR-135 b的表达和功能。暴露于香烟烟雾和NTHi引起强烈的肺部炎症，但仅在暴露于香烟烟雾的小鼠的肺部观察到miR-135 b表达增加。使用IL-1 R1敲除小鼠，我们表明miR-135 b表达是IL-1 R1依赖性的。一系列体外实验证实了IL-1 R1在调节miR-135 b表达中的作用。在小鼠胚胎成纤维细胞（NIH 3 T3）和肺上皮细胞（FE 1）中IL-1 R1通路的体外激活导致miR-135 b增加，这被IL-1 R1拮抗剂或小干扰RNA介导的IL-1 R1表达沉默阻断。在NIH 3 T3细胞中过表达成熟miR-135 b（pEGP-mmu-mir-135 b）导致内源性IL-1 R1表达水平的抑制。用含有小鼠IL-1 R1的3 'UTR的荧光素酶报告载体瞬时转染的pEGP-mmu-miR-135 b细胞显示降低的荧光素酶活性。最后，我们证明了miR-135 b靶向IL-1刺激的Caspase-1活化，Caspase-1是IL-1b的IL-1 R1下游活化剂，导致抑制活性形式的IL-1b蛋白的合成。这些结果表明，在香烟烟雾诱导的炎症过程中，miR-135 b的表达受到IL-1 R1的调节，通过调节反馈机制来解决炎症。免疫学杂志，2013，190：3679-3686。
Although microRNA-135b (miR-135b) is known to be associated with cancer, with recent work showing that it is massively induced in the pulmonary tissues of mice challenged with nanoparticles suggests a critical role for this microRNA in mediating inflammatory response. In this study, we investigated the expression and function of miR-135b in mice exposed to cigarette smoke or nontypeable Haemophilus influenzae (NTHi). Exposure to both cigarette smoke and NTHi elicited robust lung inflammation, but increased miR-135b expression was observed only in the lungs of cigarette smoke-exposed mice. Using IL-1R1 knockout mice, we show that miR-135b expression is IL-1R1 dependent. A series of in vitro experiments confirmed the role of IL-1R1 in regulating miR-135b expression. In vitro activation of the IL-1R1 pathway in mouse embryonic fibroblast (NIH3T3) and lung epithelial (FE1) cells resulted in increased miR-135b, which was blocked by IL-1R1 antagonists or small interfering RNA-mediated silencing of IL-1R1 expression. Overexpression of mature miR-135b in NIH3T3 cells (pEGP-mmu-mir-135b) resulted in the suppression of endogenous levels of IL-1R1 expression. pEGP-mmu-miR-135b cells transiently transfected with luciferase reporter vector containing the 3'UTR of mouse IL-1R1 showed reduced luciferase activity. Finally, we demonstrate that miR-135b targets IL-1-stimulated activation of Caspase-1, the IL-1R1 downstream activator of IL-1b leading to suppressed synthesis of the active form of IL-1b protein. These results suggest that miR-135b expression during cigarette smoke-induced inflammation is regulated by IL-1R1 in a regulatory feedback mechanism to resolve inflammation. The Journal of Immunology, 2013, 190: 3679-3686.