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

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Abstract
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.

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