miR-155 Modulates Cockroach Allergen- and Oxidative Stress Induced Cyclooxygenase-2 in Asthma

Exposure to cockroach allergen is a strong risk factor for developing asthma. Asthma has been associated with allergen-induced airway epithelial damage and heightened oxidant stress. In this study, we investigated cockroach allergen induced oxidative stress in airway epithelium and its underlying mechanisms. We found that cockroach extract (CRE) could induce reactive oxygen species (ROS) production, particularly mitochondrial-derived ROS, in human bronchial epithelial cells. We then used the RT2 Profiler PCR array and identified that cyclooxygenase-2 (COX-2) was the most significantly upregulated gene related to CRE-induced oxidative stress. miR-155, predicted to target COX-2, was increased in CRE-treated human bronchial epithelial cells, and was showed to regulate COX-2 expression. Moreover, miR-155 can bind COX-2, induce COX-2 reporter activity, and maintain mRNA stability. Furthermore, CRE-treated miR-155(-/-) mice showed reduced levels of ROS and COX-2 expression in lung tissues and PGE(2) in bronchoalveolar lavage fluid compared with wild-type mice. These miR-155(-/-) mice also showed reduced lung inflammation and Th2/Th17 cytokines. In contrast, when miR-155(-/-) mice were transfected with adeno-associated virus carrying miR-155, the phenotypic changes in CRE-treated miR-155(-/-) mice were remarkably reversed, including ROS, COX-2 expression, lung inflammation, and Th2/Th17 cytokines. Importantly, plasma miR-155 levels were elevated in severe asthmatics when compared with nonasthmatics or mild-to-moderate asthmatics. These increased plasma miR-155 levels were also observed in asthmatics with cockroach allergy compared with those without cockroach allergy. Collectively, these findings suggest that COX-2 is a major gene related to cockroach allergen induced oxidative stress and highlight a novel role of miR-155 in regulating the ROS COX-2 axis in asthma.