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–Induced Mucin Production in Human Airway Epithelium Is Mediated by Cyclooxygenase-2, Prostaglandin E2 Receptors, and Cyclic AMP-Protein Kinase A Signaling
Laboratories of Molecular Carcinogenesis (T.G., C.L., R.L.), Pulmonary Pathobiology (P.N., J.B.), and Biostatistics Branch (S.P.), National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina.
We reported recently that interleukin (IL)-1
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-1–induced MUC5AC production. We found that IL-1 increased cyclooxygenase-2 (COX-2) mRNA expression and prostaglandin (PG) E2 production and that the COX-2 inhibitor celecoxib suppressed IL-1–induced MUC5AC production. Addition of exogenous PGE2 to NHTBE cultures also increased MUC5AC production and IL-1–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-1 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-1 stimulation of MUC5AC mucin production. We also observed that tumor necrosis factor (TNF)-
, 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-1, TNF-, PAF, and LPS involves COX-2– generated PGE2, activation of EP2 and/or EP4 receptor(s), and cAMP-PKA–mediated signaling.
Address correspondence to: Thomas Gray, Laboratory of Molecular Carcinogenesis, MD C4–09, PO Box 12233, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709. E-mail: grayt{at}niehs.nih.gov
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