Prostaglandin H2 induces the migration of human eosinophils through the chemoattractant receptor homologous molecule of Th2 cells, CRTH2.
The major mast cell product PGD2 is released during the allergic response and stimulates the chemotaxis of eosinophils, basophils, and Th2-type T lymphocytes. The chemoattractant receptor homologous molecule of Th2 cells (CRTH2) has been shown to mediate the chemotactic effect of PGD2. PGH2 is the common precursor of all PGs and is produced by several cells that express cyclooxygenases. In this study, we show that PGH2 selectively stimulates human peripheral blood eosinophils and basophils but not neutrophils, and this effect is prevented by the CRTH2 receptor antagonist (+)-3-[[(4-fluorophenyl)sulfonyl] methyl amino]-1,2,3,4-tetrahydro-9H-carbazole-9-acetic acid (Cay10471) but not by the hematopoietic PGD synthase inhibitor 4-benzhydryloxy-1-[3-(1H-tetrazol-5-yl)-propyl]piperidine (HQL79). In chemotaxis assays, eosinophils showed a pronounced migratory response toward PGH2, but eosinophil degranulation was inhibited by PGH2. Moreover, collagen-induced platelet aggregation was inhibited by PGH2 in platelet-rich plasma, which was abrogated in the presence of the D-type prostanoid (DP) receptor antagonist 3-[(2-cyclohexyl-2-hydroxyethyl)amino]-2,5-dioxo-1-(phenylmethyl)-4-imidazolidine-heptanoic acid (BWA868c). Each of these effects of PGH2 was enhanced in the presence of plasma and/or albumin. In eosinophils, PGH2-induced calcium ion (Ca2+) flux was subject to homologous desensitization with PGD2. Human embryo kidney (HEK)293 cells transfected with human CRTH2 or DP likewise responded with Ca2+ flux, and untransfected HEK293 cells showed no response. These data indicate that PGH2 causes activation of the PGD2 receptors CRTH2 and DP via a dual mechanism: by interacting directly with the receptors and/or by giving rise to PGD2 after catalytic conversion by plasma proteins.
Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitaetsplatz 4. A-8010 Graz, Austria.
Rufina
R
Schuligoi
Miriam
M
Sedej
Maria
M
Waldhoer
Anela
A
Vukoja
Eva M
EM
Sturm
Irmgard T
IT
Lippe
Bernhard A
BA
Peskar
Akos
A
Heinemann
D001491:Basophils / Q000187:drug effects / Q000502:physiology; D001798:Blood Proteins / Q000494:pharmacology / Q000502:physiology; D002118:Calcium / Q000502:physiology; D002227:Carbazoles / Q000494:pharmacology; D002413:Cations, Divalent; D015550:Cell Degranulation; D002460:Cell Line; D002633:Chemotaxis; D003094:Collagen / Q000378:metabolism; D004804:Eosinophils / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D006827:Hydantoins / Q000494:pharmacology; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism; D054834:Lipocalins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology; D044262:Prostaglandin H2 / Q000494:pharmacology / Q000502:physiology*; D011971:Receptors, Immunologic / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D011982:Receptors, Prostaglandin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology
C116322:4-benzhydryloxy-1-(3-(1H-tetrazol-5-yl-)-propyl)piperidine; D001798:Blood Proteins; C533609:CAY 10471; D002227:Carbazoles; D002413:Cations, Divalent; D006827:Hydantoins; D054834:Lipocalins; D010880:Piperidines; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D013449:Sulfonamides; C058848:BW A868C; D044262:Prostaglandin H2; D003094:Collagen; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase; D002118:Calcium; C036293:prostaglandin D2 receptor