Differential Regulation of ATP- and UTP-Evoked Prostaglandin E and IL-6 Production from Human Airway Epithelial Cells

The airway epithelial cells (AECs) lining the conducting passageways of the lung secrete a variety of immunomodulatory factors. Among these, PGE limits lung inflammation and promotes bronchodilation. By contrast, IL-6 drives intense airway inflammation, remodeling, and fibrosis. The signaling that differentiates the production of these opposing mediators is not understood. In this study, we find that the production of PGE and IL-6 following stimulation of human AECs by the damage-associated molecular pattern extracellular ATP shares a common requirement for Ca release-activated Ca (CRAC) channels. ATP-mediated synthesis of PGE required activation of metabotropic P2Y receptors and CRAC channel-mediated cytosolic phospholipase A signaling. By contrast, ATP-evoked synthesis of IL-6 occurred via activation of ionotropic P2X receptors and CRAC channel-mediated calcineurin/NFAT signaling. In contrast to ATP, which elicited the production of both PGE and IL-6, the uridine nucleotide, UTP, stimulated PGE but not IL-6 production. These results reveal that human AECs employ unique receptor-specific signaling mechanisms with CRAC channels as a signaling nexus to regulate release of opposing immunomodulatory mediators. Collectively, our results identify P2Y receptors, CRAC channels, and P2X receptors as potential intervention targets for airway diseases.