miR-27a regulates inflammatory response of macrophages by targeting IL-10.
Although microRNAs were shown to participate in innate immune responses, it is not completely understood how they regulate negative immunomodulatory events. IL-10 is an important anti-inflammatory mediator that prevents excessive inflammation and associated immunological pathologies. Although the regulation of IL-10 expression has been well studied at both the transcriptional and translational levels, it is less clear how microRNAs control IL-10 expression during inflammation. In this study, we found that miR-27a is downregulated in macrophages following stimulation through TLR2 and TLR4, but not TLR3. Upregulation of miR-27a enhanced the expression of proinflammatory cytokines in TLR2/4-activated macrophages. Conversely, knockdown of miR-27a diminished cytokine expression. Mechanistically, we found that miR-27a negatively regulates IL-10 expression; upregulation of miR-27a decreases, whereas downregulation of miR-27a increases, IL-10 expression in activated macrophages. Likely due to the decreased expression of IL-10, upregulation of miR-27a diminished IL-10-dependent STAT3 phosphorylation in TLR4-activated macrophages. Consistent with IL-10 being a potential mediator for the role of miR-27a in the immune response, blocking IL-10 abolished the enhancing effect of miR-27a on TLR4-activated inflammation. In conclusion, our study identified miR-27a downregulation as a negative-regulatory mechanism that prevents overly exuberant TLR2- and TLR4-driven inflammatory responses.
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294.
Na
N
Xie
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294.
Huachun
H
Cui
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294.
Sami
S
Banerjee
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294.
Zheng
Z
Tan
Department of Medicine, escola Paulista de Medicina, Federal University of Sao Paulo, Sao Paulo, SP, Brazil 04039 032.
Reinaldo
R
Salomao
University of Missouri Kansas City, Kansas City, MO 64108.
Mingui
M
Fu
Wake Forest School of Medicine, Winston-Salem, NC 27157.
Edward
E
Abraham
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294.
Victor J
VJ
Thannickal
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294.
Gang
G
Liu
D000818:Animals; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology / Q000473:pathology; D016753:Interleukin-10 / Q000276:immunology*; D008070:Lipopolysaccharides / Q000633:toxicity; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000276:immunology*; D050796:STAT3 Transcription Factor / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000276:immunology
C508609:IL10 protein, human; C556062:IL10 protein, mouse; D008070:Lipopolysaccharides; C531388:MIRN27 microRNA, human; D035683:MicroRNAs; C540674:Mirn27 microRNA, mouse; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; C495342:TLR2 protein, human; C495345:TLR4 protein, human; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C440499:lipopolysaccharide, Escherichia coli O111 B4; D016753:Interleukin-10