title: MiR-146a potentially promotes IVIg-mediated inhibition of TLR4 signaling in LPS-activated human monocytes.
abstract: IVIg is used as an immunomodulatory agent in inflammatory disorders such as sepsis. IVIg also affects monocyte differentiation and functions, two processes in which microRNAs play a crucial role. Monocytes detect microorganisms through pathogen recognition receptors (PRRs) such as TLR4. MiR-146a has been shown to supress NF-κB and IRF3 activity, two key components of TLR4 signaling. To evaluate whether miR-146a is involved in the anti-inflammatory effects of IVIg, monocytes were treated with LPS or IVIg alone or, alternately, first activated with LPS followed by washing and addition of IVIg. MiR-146a, IRF3, TNF-α, IL-1β, IL-6, IL-10, IFN-β, TGF-β1 and IL-1Ra expression was analyzed by qPCR, while IRAK1, TRAF6 and IκBα expression was measured by Western blotting. We found that addition of IVIg to LPS-activated monocytes significantly upregulated the expression of miR-146a, which was associated with a significant reduction in the expression of its targets IRF3 and its regulated gene IFN-β. Furthermore, expression of IRAK1, TRAF6, and consequently NF-κB activation, was also reduced in LPS-activated monocytes following addition of IVIg, whereas TGF-β1, IL-10 and IL-1Ra were increased. Our results thus suggest that miR-146a is a mediator of IVIg effects in inflammatory disorders, point to an important role for miR-146a in the control of inflammation during sepsis and highlight a new mechanism by which IVIg exerts its anti-inflammatory effects in sepsis.
authors.affiliation: Department of Research and Development, Héma-Québec, Québec (Qc), Canada; Department of Biochemistry, Microbiology and Bioinformatics, Laval University, Québec (Qc), Canada. Electronic address: lionel.loubaki@hema-quebec.qc.ca.
authors.forename: Lionel
authors.initials: L
authors.lastname: Loubaki
authors.affiliation: Department of Research and Development, Héma-Québec, Québec (Qc), Canada; Department of Biochemistry, Microbiology and Bioinformatics, Laval University, Québec (Qc), Canada.
authors.forename: Dominique
authors.initials: D
authors.lastname: Chabot
authors.affiliation: Department of Research and Development, Héma-Québec, Québec (Qc), Canada.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Paré
authors.affiliation: Department of Research and Development, Héma-Québec, Québec (Qc), Canada.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Drouin
authors.affiliation: Department of Research and Development, Héma-Québec, Québec (Qc), Canada; Department of Biochemistry, Microbiology and Bioinformatics, Laval University, Québec (Qc), Canada.
authors.forename: Renée
authors.initials: R
authors.lastname: Bazin
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000494:pharmacology*; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides / Q000276:immunology; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects / Q000276:immunology*; D016328:NF-kappa B / Q000378:metabolism; D018805:Sepsis / Q000276:immunology* / Q000628:therapy; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; C494232:IRF3 protein, human; D016756:Immunoglobulins, Intravenous; D050838:Interferon Regulatory Factor-3; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; C495345:TLR4 protein, human; D048029:TNF Receptor-Associated Factor 6; C000604754:Tifab protein, human; D051197:Toll-Like Receptor 4; C507768:IRAK1 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases
keywords: IFN-β; IVIg; MiR-146a; Monocytes; Sepsis