MicroRNA-146a and microRNA-146b expression and anti-inflammatory function in human airway smooth muscle

• Published in: American journal of physiology. Lung cellular and molecular physiology Vol. 307; no. 9; pp. L727 - L734
• Main Authors: Comer, Brian S., Camoretti-Mercado, Blanca, Kogut, Paul C., Halayko, Andrew J., Solway, Julian, Gerthoffer, William T.
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.11.2014
• Subjects: Asthma; Asthma - genetics; Asthma - metabolism; Asthma - pathology; Cyclooxygenase 2 - genetics; Cyclooxygenase 2 - metabolism; ELAV Proteins - genetics; ELAV Proteins - metabolism; Gene expression; Gene Expression Regulation; Humans; Inflammation - genetics; Inflammation - metabolism; Inflammation - pathology; Interferon-gamma - pharmacology; Interleukin-1beta - biosynthesis; Interleukin-1beta - pharmacology; Lung diseases; MicroRNAs; MicroRNAs - antagonists & inhibitors; MicroRNAs - genetics; MicroRNAs - metabolism; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - metabolism; Myocytes, Smooth Muscle - pathology; Pathogenesis; Physiology; Primary Cell Culture; Respiratory Mucosa - drug effects; Respiratory Mucosa - metabolism; Respiratory Mucosa - pathology; RNA, Small Interfering - genetics; RNA, Small Interfering - metabolism; Signal Transduction; Tumor Necrosis Factor-alpha - pharmacology; human antigen R; inflammation; cyclooxygenase-2; interleukin-1β; miRNA-146
• ISSN: 1040-0605; 1522-1504; 1522-1504
• DOI: 10.1152/ajplung.00174.2014

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.