Journal
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
Volume 52, Issue 4, Pages 438-447Publisher
AMER THORACIC SOC
DOI: 10.1165/rcmb.2014-0129OC
Keywords
asthma; airway smooth muscle; cyclooxygenase-2; cytomix; PGE(2); microRNA
Funding
- National Institutes of Health [HL077726, HL097805, HL092588]
- Canada Research Chairs program
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Cyclooxygenase-2 (COX-2) expression and PGE(2) secretion from human airway smooth muscle cells (hASMCs) may contribute to beta(2)-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 PGE(2) 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-1 beta, TNF-alpha, and IFN-gamma). A greater elevation of COX-2 mRNA, COX-2 protein, and PGE(2) 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-kappa B 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 PGE(2) 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, beta 2-adrenoceptor hyporesponsiveness in patients with asthma.
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