title: MicroRNA-146a and microRNA-146b expression and anti-inflammatory function in human airway smooth muscle.
abstract: MicroRNA (miR)-146a and miR-146b are negative regulators of inflammatory gene expression in lung fibroblasts, epithelial cells, monocytes, and endothelial cells. The abundance of cyclooxygenase-2 (COX-2) and IL-1β is negatively regulated by the miR-146 family, suggesting miR-146a and/or miR-146b might modulate inflammatory mediator expression in airway smooth muscle thereby contributing to pathogenesis of asthma. To test this idea we compared miR-146a and miR-146b expression in human airway smooth muscle cells (hASMCs) from nonasthmatic and asthmatic subjects treated with cytomix (IL-1β, TNF-α, and IFNγ) and examined the miRNAs' effects on COX-2 and IL-1β expression. We found that cytomix treatment elevated miR-146a and miR-146b abundance. Induction with cytomix was greater than induction with individual cytokines, and asthmatic cells exhibited higher levels of miR-146a expression following cytomix treatment than nonasthmatic cells. Transfection of miR-146a or miR-146b mimics reduced COX-2 and IL-1β expression. A miR-146a inhibitor increased COX-2 and IL-1β expression, but a miR-146b inhibitor was ineffective. Repression of COX-2 and IL-1β expression by miR-146a correlated with reduced abundance of the RNA-binding protein human antigen R. These results demonstrate that miR-146a and miR-146b expression is inducible in hASMCs by proinflammatory cytokines and that miR-146a expression is greater in asthmatic cells. Both miR-146a and miR-146b can negatively regulate COX-2 and IL-1β expression at pharmacological levels, but loss-of-function studies showed that only miR-146a is an endogenous negative regulator in hASMCs. The results suggest miR-146 mimics may be an attractive candidate for further preclinical studies as an anti-inflammatory treatment of asthma.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of South Alabama, Mobile, Alabama;
authors.forename: Brian S
authors.initials: BS
authors.lastname: Comer
authors.affiliation: Center for Personalized Medicine and Genomics, Division of Allergy and Immunology, Department of Internal Medicine, University of South Florida College of Medicine, Tampa, Florida;
authors.forename: Blanca
authors.initials: B
authors.lastname: Camoretti-Mercado
authors.affiliation: Department of Medicine and Institute for Translational Medicine, University of Chicago, Chicago, Illinois;
authors.forename: Paul C
authors.initials: PC
authors.lastname: Kogut
authors.affiliation: Departments of Physiology and Pathophysiology, and Internal Medicine, University of Manitoba, Winnipeg, Manitoba, Canada; Biology of Breathing Group, Manitoba Institute of Child Health, Winnipeg, Manitoba, Canada; and.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Halayko
authors.affiliation: Department of Medicine and Institute for Translational Medicine, University of Chicago, Chicago, Illinois; Department of Pediatrics, Institute of Translational Medicine, University of Chicago, Chicago, Illinois.
authors.forename: Julian
authors.initials: J
authors.lastname: Solway
authors.affiliation: Department of Biochemistry and Molecular Biology, University of South Alabama, Mobile, Alabama; wgerthoffer@southalabama.edu.
authors.forename: William T
authors.initials: WT
authors.lastname: Gerthoffer
mesh_terms: D001249:Asthma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism; D051959:ELAV Proteins / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007371:Interferon-gamma / Q000494:pharmacology; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000494:pharmacology; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D061251:Primary Cell Culture; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D051959:ELAV Proteins; D053583:Interleukin-1beta; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human
keywords: cyclooxygenase-2; human antigen R; inflammation; interleukin-1β; miRNA-146