title: Interaction of eosinophils with endothelial cells is modulated by prostaglandin EP4 receptors.
abstract: Eosinophil extravasation across the endothelium is a key feature of allergic inflammation. Here, we investigated the role of PGE(2) and its receptor, E-type prostanoid receptor (EP)-4, in the regulation of eosinophil interaction with human pulmonary microvascular endothelial cells. PGE(2) and the EP4 receptor agonist ONO AE1-329 significantly reduced eotaxin-induced eosinophil adhesion to fibronectin, and formation of filamentous actin and gelsolin-rich adhesive structures. These inhibitory effects were reversed by a selective EP4 receptor antagonist, ONO AE3-208. PGE(2) and the EP4 agonist prevented the activation and cell-surface clustering of β2 integrins, and L-selectin shedding of eosinophils. Under physiological flow conditions, eosinophils that were treated with the EP4 agonist showed reduced adhesion to endothelial monolayers upon stimulation with eotaxin, as well as after TNF-α-induced activation of the endothelial cells. Selective activation of EP1, EP2, and EP3 receptors did not alter eosinophil adhesion to endothelial cells, whereas the EP4 antagonist prevented PGE(2) from decreasing eosinophil adhesion. Finally, eosinophil transmigration across thrombin- and TNF-α-activated endothelial cells was effectively reduced by the EP4 agonist. These data suggest that PGE(2) -EP4 signaling might be protective against allergic responses by inhibiting the interaction of eosinophils with the endothelium and might hence be a useful therapeutic option for controlling inappropriate eosinophil infiltration.
authors.affiliation: Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria.
authors.forename: Viktoria
authors.initials: V
authors.lastname: Konya
authors.forename: Sonia
authors.initials: S
authors.lastname: Philipose
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Bálint
authors.forename: Andrea
authors.initials: A
authors.lastname: Olschewski
authors.forename: Gunther
authors.initials: G
authors.lastname: Marsche
authors.forename: Eva M
authors.initials: EM
authors.lastname: Sturm
authors.forename: Rudolf
authors.initials: R
authors.lastname: Schicho
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: D018821:CD18 Antigens / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D002450:Cell Communication; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D054413:Chemokine CCL11 / Q000494:pharmacology; D003517:Cyclopentanes / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D004804:Eosinophils / Q000166:cytology / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism; D005434:Flow Cytometry; D018260:Gelsolin / Q000378:metabolism; D006801:Humans; D019041:L-Selectin / Q000378:metabolism; D008738:Methyl Ethers; D018613:Microscopy, Confocal; D009281:Naphthalenes / Q000494:pharmacology; D010654:Phenylbutyrates / Q000494:pharmacology; D058306:Receptors, Prostaglandin E, EP1 Subtype / Q000378:metabolism; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000378:metabolism; D058308:Receptors, Prostaglandin E, EP3 Subtype / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013864:Thioglycolates / Q000494:pharmacology; D013917:Thrombin / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: C487890:4-(4-cyano-2-(2-(4-fluoronaphthalen-1-yl)propionylamino)phenyl)butyric acid; D018821:CD18 Antigens; D054413:Chemokine CCL11; D003517:Cyclopentanes; D005353:Fibronectins; D018260:Gelsolin; D008738:Methyl Ethers; D009281:Naphthalenes; C461399:ONO-AE1-329; C545644:PTGER2 protein, human; D010654:Phenylbutyrates; D058306:Receptors, Prostaglandin E, EP1 Subtype; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058308:Receptors, Prostaglandin E, EP3 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013864:Thioglycolates; D014409:Tumor Necrosis Factor-alpha; D019041:L-Selectin; D013917:Thrombin; D015232:Dinoprostone