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Front Immunol. 2018 Mar 9;9:293. doi: 10.3389/fimmu.2018.00293. eCollection 2018.

Regulation of Human Natural Killer Cell IFN-γ Production by MicroRNA-146a via Targeting the NF-κB Signaling Pathway.

Wang H1,2, Zhang Y1, Wu X1,3, Wang Y1, Cui H1,4, Li X1, Zhang J5, Tun N1, Peng Y6, Yu J1,7,8.

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The Ohio State University Comprehensive Cancer Center, Columbus, OH, United States.
Department of Pathology, the First Affiliated Hospital, Chinese PLA General Hospital, Beijing, China.
The First Affiliated Hospital of Soochow University, Suzhou, China.
Department of Obstetrics and Gynecology, Daping Hospital, Army Medical School, Chongqing, China.
Department of Bioinformatics, The Ohio State University, Columbus, OH, United States.
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, United States.
The James Cancer Hospital, Columbus, OH, United States.


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.


IFN-γ; IRAK1; NF-κB; TRAF6; miR-146a; microRNA; natural killer cells

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