Interleukin-1β–Induced Mucin Production in Human Airway Epithelium Is Mediated by Cyclooxygenase-2, Prostaglandin E2 Receptors, and Cyclic AMP-Protein Kinase A Signaling

Publisher Website
Google Scholar
Abstract
We reported recently that interleukin (IL)-1β exposure resulted in a prolonged increase in MUC5AC mucin production in normal, well differentiated, human tracheobronchial epithelial (NHTBE) cell cultures, without significantly increasing MUC5AC mRNA (Am J Physiol 286:L320–L330, 2004). The goal of the present study was to elucidate the signaling pathways involved in IL-1β–induced MUC5AC production. We found that IL-1β increased cyclooxygenase-2 (COX-2) mRNA expression and prostaglandin (PG) E2 production and that the COX-2 inhibitor celecoxib suppressed IL-1β–induced MUC5AC production. Addition of exogenous PGE2 to NHTBE cultures also increased MUC5AC production and IL-1β–induced Muc5ac hypersecretion in tracheas from wild-type but not from COX-2–/– mice. NHTBE cells expressed all four E-prostanoid (EP) receptor subtypes and misoprostol, an EP2 and EP4 agonist, increased MUC5AC production, whereas sulprostone, an EP1 and EP3 agonist, did not. Furthermore, specific protein kinase A (PKA) inhibitors blocked IL-1β and PGE2-induced MUC5AC production. However, neither inhibition of epidermal growth factor receptor (EGFR) activation with the tyrosine kinase inhibitor 4-(3-chloroanilino)-6,7-dimethoxyquinazoline HCl (AG-1478) or EGFR blocking antibody nor inhibition of extracellular signal-regulated kinase/P-38 mitogen activated protein kinases with specific inhibitors blocked IL-1β stimulation of MUC5AC mucin production. We also observed that tumor necrosis factor (TNF)-α, platelet activating factor (PAF), and lipopolysaccharide (LPS) induced COX-2 and increased MUC5AC production that was blocked by celecoxib, suggesting a common signaling pathway of inflammatory mediator-induced MUC5AC production in NHTBE cells. We conclude that the induction of MUC5AC by IL-1β, TNF-α, PAF, and LPS involves COX-2– generated PGE2, activation of EP2 and/or EP4 receptor(s), and cAMP-PKA–mediated signaling.