title: Cyclooxygenase-2 and microRNA-155 expression are elevated in asthmatic airway smooth muscle cells.
abstract: Cyclooxygenase-2 (COX-2) expression and PGE2 secretion from human airway smooth muscle cells (hASMCs) may contribute to β2-adrenoceptor hyporesponsiveness, a clinical feature observed in some patients with asthma. hASMCs from patients with asthma exhibit elevated expression of cytokine-responsive genes, and in some instances this is attributable to an altered histone code and/or microRNA expression. We hypothesized that COX-2 expression and PGE2 secretion might be elevated in asthmatic hASMCs in response to proinflammatory signals in part due to altered histone acetylation and/or microRNA expression. hASMCs obtained from nonasthmatic and asthmatic human subjects were treated with cytomix (IL-1β, TNF-α, and IFN-γ). A greater elevation of COX-2 mRNA, COX-2 protein, and PGE2 secretion was observed in the asthmatic cells. We investigated histone H3/H4-acetylation, transcription factor binding, mRNA stability, p38 mitogen-activated protein kinase signaling, and microRNA (miR)-155 expression as potential mechanisms responsible for the differential elevation of COX-2 expression. We found that histone H3/H4-acetylation and transcription factor binding to the COX-2 promoter were similar in both groups, and histone H3/H4-acetylation did not increase after cytomix treatment. Cytomix treatment elevated NF-κB and RNA polymerase II binding to similar levels in both groups. COX-2 mRNA stability was increased in asthmatic cells. MiR-155 expression was higher in cytomix-treated asthmatic cells, and we show it enhances COX-2 expression and PGE2 secretion in asthmatic and nonasthmatic hASMCs. Thus, miR-155 expression positively correlates with COX-2 expression in the asthmatic hASMCs and may contribute to the elevated expression observed in these cells. These findings may explain, at least in part, β2-adrenoceptor hyporesponsiveness in patients with asthma.
authors.affiliation: 1 Department of Biochemistry and Molecular Biology, University of South Alabama, Mobile, Alabama.
authors.forename: Brian S
authors.initials: BS
authors.lastname: Comer
authors.forename: Blanca
authors.initials: B
authors.lastname: Camoretti-Mercado
authors.forename: Paul C
authors.initials: PC
authors.lastname: Kogut
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Halayko
authors.forename: Julian
authors.initials: J
authors.lastname: Solway
authors.forename: William T
authors.initials: WT
authors.lastname: Gerthoffer
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001249:Asthma / Q000201:enzymology* / Q000473:pathology; D016022:Case-Control Studies; D002478:Cells, Cultured; D002648:Child; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D032389:Myocytes, Smooth Muscle / Q000201:enzymology*; D020871:RNA Stability; D012137:Respiratory System / Q000473:pathology; D015854:Up-Regulation; D055815:Young Adult; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D048051:p38 Mitogen-Activated Protein Kinases
keywords: PGE2; airway smooth muscle; asthma; cyclooxygenase-2; cytomix; microRNA