MicroRNA-21 limits in vivo immune response-mediated activation of the IL-12/IFN-gamma pathway, Th1 polarization, and the severity of delayed-type hypersensitivity.
MicroRNA-21 limits in vivo immune response-mediated activation of the IL-12/IFN-gamma pathway, Th1 polarization, and the severity of delayed-type hypersensitivity.
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DOI：
10.4049/jimmunol.1101235
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发表时间：
2011-09-15
期刊：
影响因子：
--
通讯作者：
Rothenberg ME
中科院分区：
文献类型：
--
作者：
Lu TX;Hartner J;Lim EJ;Fabry V;Mingler MK;Cole ET;Orkin SH;Aronow BJ;Rothenberg ME
Th 1和Th 2细胞因子之间的平衡改变是导致各种免疫炎症性疾病如哮喘的原因，但转录后机制（如由microRNA介导的那些）在调节Th细胞因子表达的相对大小和平衡中的作用在很大程度上尚未探索。在这里，我们表明，miR-21在设定对抗原的Th 1和Th 2应答之间的平衡中具有核心作用。在小鼠中靶向消融miR-21导致过敏原激发后肺嗜酸性粒细胞减少，免疫活化转录组广泛重编程，Th 1细胞因子IFNγ水平显著增加。对OVA激发的miR-21-/-小鼠进行的基于生物网络的转录组分析发现，IL-12/IFNγ途径的意外显著失调在肺部受到最显著的影响，miR-21在IFNγ信号传导和T细胞极化中发挥关键作用，与IL-12 p35中的功能性miR-21结合位点一致。为了支持这些假设，miR-21缺陷导致树突状细胞在LPS刺激后产生更多的IL-12，并且OVA攻击的CD 4 + T淋巴细胞产生增加的IFNγ和减少的IL-4。此外，miR-21的缺失显著增强了Th 1相关的迟发型皮肤超敏反应。因此，我们的研究结果将miR-21定义为Th 1与Th 2反应的主要调节因子，定义了调节极化免疫炎症反应的新机制。
An altered balance between Th1 and Th2 cytokines is responsible for a variety of immuno-inflammatory disorders such as asthma, yet the role of post-transcriptional mechanisms, such as those mediated by microRNAs, in adjusting the relative magnitude and balance of Th cytokine expression have been largely unexplored. Here we show that miR-21 has a central role in setting a balance between Th1 and Th2 responses to antigens. Targeted ablation of miR-21 in mice led to reduced lung eosinophilia after allergen challenge, with a broadly reprogrammed immunoactivation transcriptome, and significantly increased levels of the Th1 cytokine IFNγ. Biological network-based transcriptome analysis of OVA-challenged miR-21-/-mice identified an unexpected prominent dysregulation of IL-12/IFNγ pathways as the most significantly affected in the lungs with a key role for miR-21 in IFNγ signaling and T-cell polarization, consistent with a functional miR-21 binding site in IL-12p35. In support of these hypotheses, miR-21 deficiency led dendritic cells to produce more IL-12 after LPS stimulation, and OVA-challenged CD4+ T lymphocytes to produce increased IFNγ and decreased IL-4. Further, loss of miR-21 significantly enhanced the Th1-associated delayed-type hypersensitivity cutaneous responses. Thus, our results define miR-21 as a major regulator of Th1 vs. Th2 responses, defining a new mechanism for regulating polarized immuno-inflammatory responses.
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影响因子：
64.8
作者：
Baek, Daehyun;Villen, Judit;Shin, Chanseok;Camargo, Fernando D.;Gygi, Steven P.;Bartel, David P.
通讯作者：
Bartel, David P.
DOI：
10.4049/jimmunol.0803560
发表时间：
2009-04-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Lu TX;Munitz A;Rothenberg ME
通讯作者：
Rothenberg ME
影响因子：
14.9
作者：
Chen C;Ridzon DA;Broomer AJ;Zhou Z;Lee DH;Nguyen JT;Barbisin M;Xu NL;Mahuvakar VR;Andersen MR;Lao KQ;Livak KJ;Guegler KJ
通讯作者：
Guegler KJ
DOI：
10.1073/pnas.87.14.5238
发表时间：
1990-07-01
影响因子：
11.1
作者：
FARBER, JM
通讯作者：
FARBER, JM
DOI：
10.1073/pnas.0914703107
发表时间：
2010-05-04
影响因子：
11.1
作者：
Chang, JiHoon;Voorhees, Timothy J.;Chang, Cheong-Hee
通讯作者：
Chang, Cheong-Hee