title: miR-17 overexpression in cystic fibrosis airway epithelial cells decreases interleukin-8 production.
abstract: Interleukin (IL)-8 levels are higher than normal in cystic fibrosis (CF) airways, causing neutrophil infiltration and non-resolving inflammation. Overexpression of microRNAs that target IL-8 expression in airway epithelial cells may represent a therapeutic strategy for cystic fibrosis. IL-8 protein and mRNA were measured in cystic fibrosis and non-cystic fibrosis bronchoalveolar lavage fluid and bronchial brushings (n=20 per group). miRNAs decreased in the cystic fibrosis lung and predicted to target IL-8 mRNA were quantified in βENaC-transgenic, cystic fibrosis transmembrane conductance regulator (Cftr)-/- and wild-type mice, primary cystic fibrosis and non-cystic fibrosis bronchial epithelial cells and a range of cystic fibrosis versus non-cystic fibrosis airway epithelial cell lines or cells stimulated with lipopolysaccharide, Pseudomonas-conditioned medium or cystic fibrosis bronchoalveolar lavage fluid. The effect of miRNA overexpression on IL-8 protein production was measured. miR-17 regulates IL-8 and its expression was decreased in adult cystic fibrosis bronchial brushings, βENaC-transgenic mice and bronchial epithelial cells chronically stimulated with Pseudomonas-conditioned medium. Overexpression of miR-17 inhibited basal and agonist-induced IL-8 protein production in F508del-CFTR homozygous CFTE29o(-) tracheal, CFBE41o(-) and/or IB3 bronchial epithelial cells. These results implicate defective CFTR, inflammation, neutrophilia and mucus overproduction in regulation of miR-17. Modulating miR-17 expression in cystic fibrosis bronchial epithelial cells may be a novel anti-inflammatory strategy for cystic fibrosis and other chronic inflammatory airway diseases.
authors.affiliation: Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland Both authors contributed equally.
authors.forename: Irene K
authors.initials: IK
authors.lastname: Oglesby
authors.affiliation: Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland Both authors contributed equally.
authors.forename: Sebastian F
authors.initials: SF
authors.lastname: Vencken
authors.affiliation: Department of Translational Pulmonology, Translational Lung Research Center Heidelberg, Member of the German Center for Lung Research (DZL), University of Heidelberg, Heidelberg, Germany.
authors.forename: Raman
authors.initials: R
authors.lastname: Agrawal
authors.affiliation: Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland.
authors.forename: Kevin
authors.initials: K
authors.lastname: Gaughan
authors.affiliation: Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland.
authors.forename: Kevin
authors.initials: K
authors.lastname: Molloy
authors.affiliation: National Children's Research Centre, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland.
authors.forename: Gerard
authors.initials: G
authors.lastname: Higgins
authors.affiliation: National Children's Research Centre, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland.
authors.forename: Paul
authors.initials: P
authors.lastname: McNally
authors.affiliation: Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland.
authors.forename: Noel G
authors.initials: NG
authors.lastname: McElvaney
authors.affiliation: Department of Translational Pulmonology, Translational Lung Research Center Heidelberg, Member of the German Center for Lung Research (DZL), University of Heidelberg, Heidelberg, Germany.
authors.forename: Marcus A
authors.initials: MA
authors.lastname: Mall
authors.affiliation: Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland cmgreene@rcsi.ie.
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Greene
mesh_terms: D000328:Adult; D000818:Animals; D001980:Bronchi / Q000166:cytology; D001992:Bronchoalveolar Lavage Fluid; D002452:Cell Count; D002460:Cell Line; D003550:Cystic Fibrosis / Q000235:genetics / Q000276:immunology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D020556:Neutrophil Infiltration; D055815:Young Adult
chemical_list: C505032:CFTR protein, human; C508606:CXCL8 protein, human; D016209:Interleukin-8; C524941:MIRN17 microRNA, human; D035683:MicroRNAs; D019005:Cystic Fibrosis Transmembrane Conductance Regulator