Insulin decreases expression of the proinflammatory receptor proteinase-activated receptor-2 on human airway epithelial cells

Insulin resistance is associated with allergic sensitization and allergic asthma in human subjects2,3 and animal models.4 Recent evidence shows decreased insulin receptor expression in the airway epithelium of asthmatic patients,5 suggesting the presence of insulin resistance in the asthmatic epithelium. [...]airway inflammation in asthmatic patients could be, at least in part, the result of decrease in insulin-mediated anti-inflammatory mechanisms in the airways. Proteinase-activated receptor-2 (PAR-2) is a G protein–coupled receptor involved in the pathogenesis of a number of inflammatory conditions,E1-E6 including allergic asthma,6,7 a condition with increased PAR-2 expression on airway epithelial cells (AECs).8 Based on a previous observation that PAR-2 expression and PAR-2–mediated inflammation increase in insulin-resistant adipose tissue,E7-E9 we hypothesized that insulin regulates PAR-2 expression also in the airways. Detailed methods are described in the Methods section in this article's Online Repository at www.jacionline.org. Because high-fat diet (HFD)–induced insulin resistance modulates PAR-2 expression in adipose tissue,E7-E9 we studied PAR-2 expression in the lungs of HFD-fed mice. [...]the FOXO-1 inhibitor AS1842856 prevented insulin deficiency–induced PAR-2 upregulation in submerged (Fig 2, G) and ALI cultures of AECs (Fig 2, H).