Evidence that PAR2-triggered prostaglandin E2 (PGE2) formation involves the ERK-cytosolic phospholipase A2-COX-1-microsomal PGE synthase-1 cascade in human lung epithelial cells.
We investigated possible involvement of three isozymes of prostaglandin E synthase (PGES), microsomal PGES-1 (mPGES-1), mPGES-2 and cytosolic PGES (cPGES) in COX-2-dependent prostaglandin E(2) (PGE(2)) formation following proteinase-activated receptor-2 (PAR2) stimulation in human lung epithelial cells. PAR2 stimulation up-regulated mPGES-1 as well as COX-2, but not mPGES-2 or cPGES, leading to PGE(2) formation. The PAR2-triggered up-regulation of mPGES-1 was suppressed by inhibitors of COX-1, cytosolic phospholipase A(2) (cPLA(2)) and MEK, but not COX-2. Finally, a selective inhibitor of mPGES-1 strongly suppressed the PAR2-evoked PGE(2) formation. PAR2 thus appears to trigger specific up-regulation of mPGES-1 that is dependent on prostanoids formed via the MEK/ERK/cPLA(2)/COX-1 pathway, being critical for PGE(2) formation.
Nagataki
Mami
M
Division of Physiology and Pathophysiology, Kinki University School of Pharmacy, Higashi-Osaka, Japan.
Moriyuki
Kazumi
K
Sekiguchi
Fumiko
F
Kawabata
Atsufumi
A
D001095:Arachidonic Acids / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D002478:Cells, Cultured; D051545:Cyclooxygenase 1 / Q000187:drug effects / Q000378:metabolism*; D015232:Dinoprostone / Q000096:biosynthesis*; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D019746:Intramolecular Oxidoreductases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D007527:Isoenzymes / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000166:cytology; D009570:Nitriles / Q000494:pharmacology; D009578:Nitrobenzenes / Q000494:pharmacology; D054510:Phospholipases A2, Cytosolic / Q000187:drug effects / Q000378:metabolism*; D000071876:Prostaglandin-E Synthases; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D044464:Receptor, PAR-2 / Q000187:drug effects / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D002722:Chlorobenzenes
D001095:Arachidonic Acids; D002070:Butadienes; D051545:Cyclooxygenase 1; D015232:Dinoprostone; D048049:Extracellular Signal-Regulated MAP Kinases; D007211:Indoles; D019746:Intramolecular Oxidoreductases; D007527:Isoenzymes; D009570:Nitriles; D009578:Nitrobenzenes; D054510:Phospholipases A2, Cytosolic; D000071876:Prostaglandin-E Synthases; D011720:Pyrazoles; D012333:RNA, Messenger; D044464:Receptor, PAR-2; D013449:Sulfonamides; C115461:SC 560; C113580:U 0126; C081565:arachidonyltrifluoromethane; C060893:MK-886; D002722:Chlorobenzenes; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; C000605862:PTGES protein, human; C000605863:PTGES2 protein, human