Differential Regulation of ATP- and UTP-Evoked Prostaglandin E₂ and IL-6 Production from Human Airway Epithelial...

The airway epithelial cells (AECs) lining the conducting passageways of the lung secrete a variety of immunomodulatory factors. Among these, PGE₂ 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 PGE₂ and IL-6 following stimulation of human AECs by the damage-associated molecular pattern extracellular ATP shares a common requirement for Ca²⁺ release-activated Ca²⁺ (CRAC) channels. ATP-mediated synthesis of PGE₂ required activation of metabotropic P2Y₂ receptors and CRAC channel-mediated cytosolic phospholipase A₂ 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 PGE₂ and IL-6, the uridine nucleotide, UTP, stimulated PGE₂ 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 P2Y₂ receptors, CRAC channels, and P2X receptors as potential intervention targets for airway diseases.