title: MicroRNA-146 represses endothelial activation by inhibiting pro-inflammatory pathways.
abstract: Activation of inflammatory pathways in the endothelium contributes to vascular diseases, including sepsis and atherosclerosis. We demonstrate that miR-146a and miR-146b are induced in endothelial cells upon exposure to pro-inflammatory cytokines. Despite the rapid transcriptional induction of the miR-146a/b loci, which is in part mediated by EGR-3, miR-146a/b induction is delayed and sustained compared to the expression of leukocyte adhesion molecules, and in fact coincides with the down-regulation of inflammatory gene expression. We demonstrate that miR-146 negatively regulates inflammation. Over-expression of miR-146a blunts endothelial activation, while knock-down of miR-146a/b in vitro or deletion of miR-146a in mice has the opposite effect. MiR-146 represses the pro-inflammatory NF-κB pathway as well as the MAP kinase pathway and downstream EGR transcription factors. Finally, we demonstrate that HuR, an RNA binding protein that promotes endothelial activation by suppressing expression of endothelial nitric oxide synthase (eNOS), is a novel miR-146 target. Thus, we uncover an important negative feedback regulatory loop that controls pro-inflammatory signalling in endothelial cells that may impact vascular inflammatory diseases.
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, Canada.
authors.forename: Henry S
authors.initials: HS
authors.lastname: Cheng
authors.forename: Nirojini
authors.initials: N
authors.lastname: Sivachandran
authors.forename: Andrew
authors.initials: A
authors.lastname: Lau
authors.forename: Emilie
authors.initials: E
authors.lastname: Boudreau
authors.forename: Jimmy L
authors.initials: JL
authors.lastname: Zhao
authors.forename: David
authors.initials: D
authors.lastname: Baltimore
authors.forename: Paul
authors.initials: P
authors.lastname: Delgado-Olguin
authors.forename: Myron I
authors.initials: MI
authors.lastname: Cybulsky
authors.forename: Jason E
authors.initials: JE
authors.lastname: Fish
mesh_terms: D000818:Animals; D002460:Cell Line; D016207:Cytokines / Q000276:immunology; D015536:Down-Regulation; D051959:ELAV Proteins / Q000276:immunology; D042783:Endothelial Cells / Q000276:immunology* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism; D056426:Genetic Loci; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology; D018836:Inflammation Mediators / Q000276:immunology*; D053583:Interleukin-1beta / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000276:immunology*; D020928:Mitogen-Activated Protein Kinases / Q000276:immunology; D016328:NF-kappa B / Q000276:immunology; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000276:immunology; D015533:Transcriptional Activation; D015854:Up-Regulation
chemical_list: D016207:Cytokines; D051959:ELAV Proteins; D018836:Inflammation Mediators; D053583:Interleukin-1beta; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; C534190:Mirn146 microRNA, mouse; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D020928:Mitogen-Activated Protein Kinases
keywords: atherosclerosis; endothelium; gene regulation; inflammation; microRNA