MicroRNA-92a negatively regulates Toll-like receptor (TLR)-triggered inflammatory response in macrophages by targeting MKK4 kinase.
Toll-like receptors (TLRs) play a critical role in the initiation of immune responses against invading pathogens. MicroRNAs have been shown to be important regulators of TLR signaling. In this study, we have found that the stimulation of multiple TLRs rapidly reduced the levels of microRNA-92a (miRNA-92a) and some other members of the miRNA-92a family in macrophages. miR-92a mimics significantly decreased, whereas miR-92a knockdown increased, the activation of the JNK/c-Jun pathway and the production of inflammatory cytokines in macrophages when stimulated with ligands for TLR4. Furthermore, mitogen-activated protein kinase kinase 4 (MKK4), a kinase that activates JNK/stress-activated protein kinase, was found to be directly targeted by miR-92a. Similar to the effects of the miR-92a mimics, knockdown of MKK4 inhibited the activation of JNK/c-Jun signaling and the production of TNF-α and IL-6. In conclusion, we have demonstrated that TLR-mediated miR-92a reduction feedback enhances TLR-triggered production of inflammatory cytokines in macrophages, thus outlining new mechanisms for fine-tuning the TLR-triggered inflammatory response.
Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China.
Lihua
L
Lai
Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China.
Yinjing
Y
Song
Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China.
Yang
Y
Liu
Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China.
Qingyun
Q
Chen
Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China.
Quan
Q
Han
Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China.
Weilin
W
Chen
Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China.
Ting
T
Pan
Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China.
Yuanyuan
Y
Zhang
Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China; National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
Xuetao
X
Cao
Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China. Electronic address: wqq@zju.edu.cn.
Qingqing
Q
Wang
D020413:3' Untranslated Regions; D000818:Animals; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D008024:Ligands; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
D020413:3' Untranslated Regions; D008024:Ligands; C541874:MIRN92 microRNA, human; D035683:MicroRNAs; C541873:Mirn92 microRNA, mouse; D034741:RNA, Small Interfering; C495345:TLR4 protein, human; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D048670:MAP Kinase Kinase 4; C482559:MAP2K4 protein, human; C482562:Map2k4 protein, mouse