title: EP4 receptor stimulation down-regulates human eosinophil function.
abstract: Accumulation of eosinophils in tissue is a hallmark of allergic inflammation. Here we observed that a selective agonist of the PGE(2) receptor EP4, ONO AE1-329, potently attenuated the chemotaxis of human peripheral blood eosinophils, upregulation of the adhesion molecule CD11b and the production of reactive oxygen species. These effects were accompanied by the inhibition of cytoskeletal rearrangement and Ca(2+) mobilization. The involvement of the EP4 receptor was substantiated by a selective EP4 antagonist, which reversed the inhibitory effects of PGE(2) and the EP4 agonist. Selective kinase inhibitors revealed that the inhibitory effect of EP4 stimulation on eosinophil migration depended upon activation of PI 3-kinase and PKC, but not cAMP. Finally, we found that EP4 receptors are expressed by human eosinophils, and are also present on infiltrating leukocytes in inflamed human nasal mucosa. These data indicate that EP4 agonists might be a novel therapeutic option in eosinophilic diseases.
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitaetsplatz 4, 8010 Graz, Austria.
authors.forename: Petra
authors.initials: P
authors.lastname: Luschnig-Schratl
authors.forename: Eva M
authors.initials: EM
authors.lastname: Sturm
authors.forename: Viktoria
authors.initials: V
authors.lastname: Konya
authors.forename: Sonia
authors.initials: S
authors.lastname: Philipose
authors.forename: Gunther
authors.initials: G
authors.lastname: Marsche
authors.forename: Eleonore
authors.initials: E
authors.lastname: Fröhlich
authors.forename: Claudia
authors.initials: C
authors.lastname: Samberger
authors.forename: Doris
authors.initials: D
authors.lastname: Lang-Loidolt
authors.forename: Stefan
authors.initials: S
authors.lastname: Gattenlöhner
authors.forename: Irmgard Th
authors.initials: IT
authors.lastname: Lippe
authors.forename: Bernhard A
authors.initials: BA
authors.lastname: Peskar
authors.forename: Rufina
authors.initials: R
authors.lastname: Schuligoi
authors.forename: Akos
authors.initials: A
authors.lastname: Heinemann
mesh_terms: D039481:CD11b Antigen / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000737:chemistry / Q000378:metabolism; D002465:Cell Movement; D003517:Cyclopentanes / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D015536:Down-Regulation; D004804:Eosinophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D054833:Isoindoles / Q000494:pharmacology; D008738:Methyl Ethers; D009297:Nasal Mucosa / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D013864:Thioglycolates / Q000494:pharmacology
chemical_list: D039481:CD11b Antigen; D015220:Calcium Channels; D003517:Cyclopentanes; D054833:Isoindoles; D008738:Methyl Ethers; C515270:N-(2-(4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo(f)isoindol-2-yl)phenyl)acetyl)benzene sulphonamide; C461399:ONO-AE1-329; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013449:Sulfonamides; D013864:Thioglycolates; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D015232:Dinoprostone; D002118:Calcium