H1 and PAR2 receptors enhance delivery of immune-competent cells and molecules by interrupting E-cadherin adhesion in epithelia.

The lung's epithelial surface is at the same time vitally exchanging gas with the environment and acting as a barrier that protects the organism from the environment. We hypothesized that activation of epithelial-cell G-protein-coupled receptors for immune-defense molecules would temporarily interrupt cadherin-dependent cell-cell adhesion of epithelial cells and thereby focally and temporarily compromise the epithelial barrier to facilitate delivery of other immune molecules and cells to challenged sites. Activation of type 1 histamine or type 2 PAR receptors on the basolateral surface of primary airway epithelial cells or L-cells expressing E-cadherin interrupted cadherin adhesion and caused approximately a 50% decrease in the epithelial barrier for 2-3 minutes. Given basic biochemical observations of others, we further hypothesized that activation of the receptors altered the barrier by phosphorylating tyrosines on an essential cadherin-complex component, beta-catenin. Y-F mutations in beta-catenin completely blocked the effects of activating the same receptors on cadherin-dependent adhesion and on the epithelial barrier. Hence, G-protein-coupled receptors responding to immune-defense molecules temporarily and focally interrupt the lung epithelial barrier by compromising cadherin-based adhesion.