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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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CD11b Antigen / metabolism
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Calcium / metabolism
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Calcium Channels / chemistry
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Calcium Channels / metabolism
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Cell Movement
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Cyclopentanes / pharmacology
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Dinoprostone / pharmacology
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Down-Regulation*
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Eosinophils / drug effects
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Eosinophils / immunology
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Eosinophils / metabolism*
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Humans
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Inflammation / metabolism
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Inflammation / pathology
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Isoindoles / pharmacology
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Methyl Ethers
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Nasal Mucosa / metabolism
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Nasal Mucosa / pathology
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Phosphatidylinositol 3-Kinases / metabolism
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Protein Kinase C / metabolism
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Protein Kinase Inhibitors / pharmacology
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Reactive Oxygen Species / metabolism
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Receptors, Prostaglandin E, EP4 Subtype / agonists
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Receptors, Prostaglandin E, EP4 Subtype / antagonists & inhibitors
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Receptors, Prostaglandin E, EP4 Subtype / metabolism*
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Sulfonamides / pharmacology
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Thioglycolates / pharmacology
Substances
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CD11b Antigen
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Calcium Channels
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Cyclopentanes
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Isoindoles
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Methyl Ethers
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N-(2-(4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo(f)isoindol-2-yl)phenyl)acetyl)benzene sulphonamide
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ONO-AE1-329
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Protein Kinase Inhibitors
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Reactive Oxygen Species
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Receptors, Prostaglandin E, EP4 Subtype
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Sulfonamides
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Thioglycolates
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Phosphatidylinositol 3-Kinases
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Protein Kinase C
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Dinoprostone
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Calcium