Regulation of Human Natural Killer Cell IFN-γ Production by MicroRNA-146a via Targeting the NF-κB Signaling Pathway.
Regulation of Human Natural Killer Cell IFN-γ Production by MicroRNA-146a via Targeting the NF-κB Signaling Pathway.
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MicroRNA-146a 通过靶向 NF-κB 信号通路调节人自然杀伤细胞 IFN-γ 的产生
DOI：
10.3389/fimmu.2018.00293
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发表时间：
2018
影响因子：
7.3
通讯作者：
Yu J
中科院分区：
文献类型：
--
作者：
Wang H;Zhang Y;Wu X;Wang Y;Cui H;Li X;Zhang J;Tun N;Peng Y;Yu J
自然杀伤(NK)细胞是一组天然的淋巴细胞，对宿主抵抗肿瘤和病毒具有重要作用。MicroRNAs(MiRNAs)在调节包括NK细胞在内的免疫细胞的反应中起着关键作用。越来越多的证据表明miR-146a参与了免疫反应的调节。然而，miR-146a调节NK细胞功能的机制在很大程度上还不清楚。在目前的研究中，我们发现miR-146a对NK细胞的功能具有内在的调节作用。在IL-12刺激或IL-12和IL-18共同刺激下，强制过表达miR-146a可显著降低人NK-92细胞株和原代人NK细胞中干扰素-γ的产生，而通过反义miR-146a下调miR-146a可显著增加人NK-92细胞和原代人NK细胞中干扰素-γ的产生。在机制上，miR-146a通过NF-γB调节干扰素-κ的产生，在NK-92细胞中，当miR-146a过表达时，通过下调NF-κBp65的磷酸化，而当抗miR-146a过表达时，通过上调NF-κBp65的磷酸化。MIR-146a直接靶向NF-κB信号通路的上游信号成分IRAK1和TRAF6。这种直接靶向机制证实了上述获得和失去功能的方法。然而，产生干扰素-γ的强亚群CD56bright NK细胞表达miR-146a的水平高于产生较弱干扰素-γ的亚群CD56dim NK细胞。我们还观察到，IL-12和IL-18的共同刺激显著增加了大量NK细胞和CD56bright亚群中miR-146a的表达，并呈时间依赖关系，与增加干扰素-γ的产生相关。这些数据表明，miR-146a对人NK细胞产生干扰素-γ具有负性作用，这一miRNA可能在防止NK细胞过度激活和过度产生干扰素-γ方面起关键作用。
Natural killer (NK) cells are one group of innate lymphocytes that are important for host defense against malignancy and viruses. MicroRNAs (miRNAs) play a critical role in regulating responses of immune cells including NK cells. Accumulating evidence suggests that miR-146a is involved in the regulation of immune responses. However, the mechanism by which miR-146a regulates NK cell function is largely unknown. In the current study, we found that miR-146a intrinsically regulated NK cell function. Forced overexpression of miR-146a decreased IFN-γ production, whereas downregulation of miR-146a by anti-miR-146a significantly enhanced IFN-γ production in the human NK-92 cell line and primary human NK cells upon stimulation with IL-12 or co-stimulation with IL-12 and IL-18. Mechanistically, miR-146a regulated IFN-γ production via NF-κB, as evidenced in NK-92 cells, by downregulation of NF-κB p65 phosphorylation when miR-146a was overexpressed but upregulation of NF-κB p65 phosphorylation when anti-miR-146a was overexpressed. miR-146a directly targeted IRAK1 and TRAF6, the upstream signaling components of the NF-κB signaling pathway. This direct targeting mechanism confirmed the above gain- and loss-of-function approaches. However, the potent IFN-γ-producing subset, CD56bright NK cells, expressed higher levels of miR-146a than the lesser IFN-γ-producing subset, CD56dim NK cells. We also observed that co-stimulation of IL-12 and IL-18 significantly increased miR-146a expression in bulk NK cells and in the CD56bright subset in a time-dependent manner, correlating with augmented IFN-γ production. These data suggest that miR-146a plays a negative role in IFN-γ production by human NK cells and this miRNA may be critical in preventing NK cells from being super activated and overproducing IFN-γ.
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影响因子：
12.3
作者：
Monticelli, Silvia;Ansel, K Mark;Xiao, Changchun;Socci, Nicholas D;Krichevsky, Anna M;Thai, To-Ha;Rajewsky, Nikolaus;Marks, Debora S;Sander, Chris;Rajewsky, Klaus;Rao, Anjana;Kosik, Kenneth S
通讯作者：
Kosik, Kenneth S
影响因子：
20.3
作者：
Fauriat, Cyril;Long, Eric O.;Bryceson, Yenan T.
通讯作者：
Bryceson, Yenan T.
影响因子：
20.3
作者：
Kannan, Yashaswini;Yu, Jianhua;Wewers, Mark D.
通讯作者：
Wewers, Mark D.
DOI：
10.1074/jbc.m109.056317
发表时间：
2009-12-11
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Nahid MA;Pauley KM;Satoh M;Chan EK
通讯作者：
Chan EK
影响因子：
--
作者：
Nakasa, Tomoyuki;Miyaki, Shigeru;Asahara, Hiroshi
通讯作者：
Asahara, Hiroshi