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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Signal Transduction for Proteinase-Activated Receptor-2-Triggered Prostaglandin E₂ Formation in Human Lung Epithelial Cells

Division of Physiology and Pathophysiology (N.K., M.N., K.N., S.K., F.S., A.K.) and Division of Biological Chemistry (T.W., S.I.), School of Pharmaceutical Sciences, Kinki University, Higashi-Osaka, Japan; Department of Pharmacology and Therapeutics (M.D.H.) and Department of Physiology and Biophysics (K.C., W.K.M.), Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada; and Research and Development Centre, Fuso Pharmaceutical Industries Ltd., Osaka, Japan (H.N.)

We investigated proteinase-activated receptor-2 (PAR₂)-triggered signal transduction pathways causing increased prostaglandin E₂ (PGE₂) formation in human lung-derived A549 epithelial cells. The PAR₂ agonist, SLIGRL-NH₂ (Ser-Leu-Ile-Gly-Arg-Leu-amide), evoked immediate cytosolic Ca²⁺ mobilization and delayed (0.5-3 h) PGE₂ formation. The PAR₂-triggered PGE₂ formation was attenuated by inhibition of the following signal pathway enzymes: cyclooxygenases 1 and 2 (COX-1 and COX-2, respectively), cytosolic Ca²⁺-dependent phospholipase A₂ (cPLA₂), the mitogen-activated protein kinases (MAPKs), mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) and p38 MAPK, Src family tyrosine kinase, epidermal growth factor (EGF) receptor tyrosine kinase (EGFRK), and protein kinase C (PKC), but not by inhibition of matrix metalloproteinases. SLIGRL-NH₂ caused prompt (5 min) and transient ERK phosphorylation, blocked in part by inhibitors of PKC and tyrosine kinases but not by an EGFRK inhibitor. SLIGRL-NH₂ also evoked a relatively delayed (15 min) and persistent (30 min) phosphorylation of p38 MAPK, blocked by inhibitors of Src and EGFRK but not by inhibitors of COX-1 or COX-2. SLIGRL-NH₂ elicited a Src inhibitor-blocked prompt (5 min) and transient phosphorylation of the EGFRK. SLIGRL-NH₂ up-regulated COX-2 protein and/or mRNA levels that were blocked by inhibition of p38 MAPK, EGFRK, Src, and COX-2 but not MEK-ERK. SLIGRL-NH₂ also caused COX-1-dependent up-regulation of microsomal PGE synthase-1 (mPGES-1). We conclude that PAR₂-triggered PGE₂ formation in A549 cells involves a coordinated up-regulation of COX-2 and mPGES-1 involving cPLA₂, increased cytosolic Ca²⁺, PKC, Src, MEK-ERK, p38 MAPK, Src-mediated EGF receptor trans-activation, and also metabolic products of both COX-1 and COX-2.

Address correspondence to: Dr. Atsufumi Kawabata, Division of Physiology and Pathophysiology, School of Pharmaceutical Sciences, Kinki University, 3-4-1 Kowakae, Higashi-Osaka 577-8502, Japan. E-mail: kawabata{at}phar.kindai.ac.jp

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