title: Prostaglandin E2 enhances interleukin-8 production via EP4 receptor in human pulmonary microvascular endothelial cells.
abstract: Prostaglandin E(2) (PGE(2)) is a bioactive prostanoid implicated in the inflammatory processes of acute lung injury/acute respiratory distress syndrome. This study investigated whether PGE(2) can induce production of interleukin (IL)-8, the major chemokine for neutrophil activation, from human pulmonary microvascular endothelial cells (HPMVECs). PGE(2) significantly enhanced IL-8 protein production with increases in IL-8 mRNA expression and intracellular cAMP levels. HPMVECs expressed only EP4 receptor mRNA. The PGE(2) effects were mimicked by a selective EP4 receptor agonist, ONO-AE1-329, and inhibited by a selective EP4 receptor antagonist, ONO-AE3-208, or a protein kinase A inhibitor, Rp-adenosine 3',5'-cyclic monophosphorothioate triethylamine salt. The specific agonist for EP1, EP2, or EP3 receptor did not induce IL-8 production. PGE(2)-induced IL-8 production was accompanied by p38 phosphorylation and was significantly inhibited by a p38 inhibitor, SB-203580, but not by an ERK1/2 inhibitor, U-0126, or a JNK inhibitor, SP-600125. Additionally, PGE(2) increased cyclooxygenase-2 expression with no change in constitutive cyclooxygenase-1 expression, suggesting possible involvement of an autocrine or paracrine manner. In conclusion, PGE(2) enhances IL-8 production via EP4 receptor coupled to G(s) protein in HPMVECs. Activation of the cAMP/protein kinase A pathway, followed by p38 activation, is essential for these mechanisms. Because neutrophils play a critical role in the inflammation of acute lung injury/acute respiratory distress syndrome, IL-8 released from the pulmonary microvasculature in response to PGE(2) may contribute to pathophysiology of this disease.
authors.affiliation: Dept. of Respiratory Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Aso
authors.forename: Satoru
authors.initials: S
authors.lastname: Ito
authors.forename: Akemi
authors.initials: A
authors.lastname: Mori
authors.forename: Masataka
authors.initials: M
authors.lastname: Morioka
authors.forename: Nobukazu
authors.initials: N
authors.lastname: Suganuma
authors.forename: Masashi
authors.initials: M
authors.lastname: Kondo
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Imaizumi
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Hasegawa
mesh_terms: D055371:Acute Lung Injury / Q000378:metabolism / Q000473:pathology; D000873:Anthracenes / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000096:biosynthesis / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000096:biosynthesis / Q000378:metabolism; D051545:Cyclooxygenase 1 / Q000096:biosynthesis; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D015232:Dinoprostone / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D016209:Interleukin-8 / Q000096:biosynthesis*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D008168:Lung / Q000098:blood supply*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008738:Methyl Ethers / Q000494:pharmacology; D055806:Microvessels / Q000166:cytology; D009281:Naphthalenes / Q000494:pharmacology; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D010654:Phenylbutyrates / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012128:Respiratory Distress Syndrome / Q000378:metabolism / Q000473:pathology; D013873:Thionucleotides / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C487890:4-(4-cyano-2-(2-(4-fluoronaphthalen-1-yl)propionylamino)phenyl)butyric acid; D000873:Anthracenes; D002070:Butadienes; D007093:Imidazoles; D016209:Interleukin-8; D008738:Methyl Ethers; D009281:Naphthalenes; D009570:Nitriles; C461399:ONO-AE1-329; D010654:Phenylbutyrates; D011725:Pyridines; D012333:RNA, Messenger; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013873:Thionucleotides; C113580:U 0126; C432165:pyrazolanthrone; C016957:adenosine-3',5'-cyclic phosphorothioate; D000242:Cyclic AMP; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D017868:Cyclic AMP-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D015232:Dinoprostone; C093642:SB 203580