miR-147, a microRNA that is induced upon Toll-like receptor stimulation, regulates murine macrophage inflammatory responses.
Toll-like receptors (TLRs) are major receptors that enable inflammatory cells to recognize invading microbial pathogens. MicroRNAs are small non-coding RNAs that play important regulatory roles in a variety of biological processes. In this study, we found that a microRNA, miR-147, was induced upon stimulation of multiple TLRs and functioned as a negative regulator of TLR-associated signaling events in murine macrophages. We first demonstrated that the NMES1 transcript was a functional primary miR-147. miR-147 was induced in LPS-stimulated mouse macrophages and under in vivo conditions in the lungs of LPS-treated mice. Expression of miR-147 was greater after cellular activation by TLR4 than after engagement of either TLR2 or TLR3, suggesting that maximal induction of miR-147 required activation of both NF-kappaB and IRF3. TLR4-induced miR-147 expression was both MyD88- and TRIF-dependent. The miR-147 promoter was responsive to TLR4 stimulation and both NF-kappaB and STAT1alpha bound to the miR-147 promoter. miR-147 mimics or induced expression of miR-147 decreased, whereas miR-147 knockdown increased inflammatory cytokine expression in macrophages stimulated with ligands to TLR2, TLR3, and TLR4. These data demonstrate a negative-feedback loop in which TLR stimulation induces miR-147 to prevent excessive inflammatory responses.
Liu
Gang
G
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Friggeri
Arnaud
A
Yang
Yanping
Y
Park
Young-Jun
YJ
Tsuruta
Yuko
Y
Abraham
Edward
E
D000818:Animals; D002460:Cell Line; D025461:Feedback, Physiological; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
D008070:Lipopolysaccharides; D035683:MicroRNAs; C544772:Mirn147 microRNA, mouse; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors