miR-147, a microRNA that is induced upon Toll-like receptor stimulation, regulates murine macrophage inflammatory responses

• Published in: Proceedings of the National Academy of Sciences - PNAS 2009-09, Vol.106 (37), p.15819-15824
• Main Authors: Liu, Gang, Friggeri, Arnaud, Yang, Yanping, Park, Young-Jun, Tsuruta, Yuko, Abraham, Edward
• Format: Article
• Language: English
• Subjects: Animals; Binding sites; Biological Sciences; Cell Line; Cell lines; Cytokines; Feedback, Physiological; Gene expression; Genes; Humans; Inflammation - genetics; Inflammation - immunology; Inflammation - metabolism; Ligands; Lipopolysaccharides - pharmacology; Lungs; Macrophages; Macrophages - drug effects; Macrophages - immunology; Macrophages - metabolism; Macrophages, Alveolar - drug effects; Macrophages, Alveolar - immunology; Macrophages, Alveolar - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; MicroRNA; MicroRNAs - biosynthesis; MicroRNAs - genetics; MicroRNAs - immunology; Peritoneal macrophages; Promoter Regions, Genetic - drug effects; Ribonucleic acid; RNA; Rodents; Studies; Toll like receptors; Toll-Like Receptor 4 - metabolism; Toll-Like Receptors - metabolism; Transfection; Up-Regulation - drug effects
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0901216106

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-κB 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-κB and STAT1α 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.