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Front. Immunol. | doi: 10.3389/fimmu.2018.00293

Regulation of human natural killer cell IFN-γ production by microRNA-146a via targeting the NF-κB signaling pathway

Hongwei Wang1, Xinxin Li1,  Jianying Zhang1, Norm Tun1,  Yong Peng2 and  Jianhua Yu1*
  • 1Comprehensive Cancer Center, The Ohio State University, United States
  • 2State Key Laboratory of Biotherapy, Sichuan University, China

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-of-function and loss-of-function approaches. However, the potent IFN-γ-producing subset, CD56bright NK cells, expressed higher levels of miR-146a than the least 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.

Keywords: Natural Killer cells, microRNA, IFN-γ, mir-146a, IRAK1, TRAF6, NF-κB

Received: 24 Sep 2017; Accepted: 01 Feb 2018.

Edited by:

Yenan Bryceson, Karolinska Institute (KI), Sweden

Reviewed by:

Frank M. Cichocki, University of Minnesota Twin Cities, United States
HONGYA HAN, Karolinska Institute (KI), Sweden  

Copyright: © 2018 Wang, Li, Zhang, Tun, Peng and Yu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Jianhua Yu, The Ohio State University, Comprehensive Cancer Center, Columbus, United States, jianhua.yu@osumc.edu