Objective-Low concentrations of prostaglandin (PG) E 2 enhance platelet aggregation, whereas high concentrations inhibit it. The effects of PGE 2 are mediated through 4 G protein-coupled receptors, termed E-type prostaglindin (EP) receptor EP1, EP2, EP3, and EP4. The platelet-stimulating effect of PGE 2 has been suggested to involve EP3 receptors. Here we analyzed the receptor usage relating to the inhibitory effect of PGE 2 . Methods and Results-Using flow cytometry, we found that human platelets expressed EP4 receptor protein. A selective EP4 agonist (ONO AE1-329) potently inhibited the platelet aggregation as induced by ADP or collagen. This effect could be completely reversed by an EP4 antagonist, but not by PGI 2 , PGD 2 , and thromboxane receptor antagonists or cyclooxygenase inhibition. Moreover, an EP4 antagonist enhanced the PGE 2 -induced stimulation of platelet aggregation, indicating a physiological antiaggregatory activity of EP4 receptors. The inhibitory effect of the EP4 agonist was accompanied by attenuated Ca 2ϩ flux, inhibition of glycoprotein IIb/IIIa, and downregulation of P-selectin. Most importantly, adhesion of platelets to fibrinogen under flow and in vitro thrombus formation were effectively prevented by the EP4 agonist. In this respect, the EP4 agonist synergized with acetylsalicylic acid. Key Words: aspirin Ⅲ pharmacology Ⅲ platelet receptor blockers Ⅲ platelets Ⅲ prostacyclin Ⅲ prostaglandins Ⅲ thromboxanes S ubjects with increased platelet reactivity are at increased prospective risk for coronary events and death. A number of pathophysiological states, such as atherosclerosis, diabetes, and metabolic syndrome, are associated with increased platelet reactivity and thrombogenic potential. Under inflammatory conditions, the synthesis of prostanoids in endothelial cells and smooth muscle cells is highly increased. Predominantly, the biosynthesis of prostaglandin (PG) E 2 is enhanced in vascular smooth muscle cells 1 and macrophages 2,3 by inflammatory mediators. Conclusion-TheseProstanoids are involved in hemostasis by differentially influencing platelet aggregation. Although thromboxane (TX) A 2 , produced in platelets, and PGH 2 , released untransformed from activated/dysfunctional endothelium, are potent stimulators of platelet aggregation, 4 PGI 2 and PGD 2 are known to inhibit platelet aggregation. 5 PGE 2 shows a biphasic, concentration-dependent effect on platelet aggregation. Although high concentrations inhibit platelet aggregation, lower concentrations enhance it. 6 -11 PGE 2 binds and activates 4 G protein-coupled receptors, EP1, EP2, EP3, and EP4. Each of these receptors has a distinct pharmacological signature and intracellular signal transduction. 12,13,14 Stimulation of the EP3 receptors results in elevation of free intracellular Ca 2ϩ levels, whereas stimulation of the EP2 and EP4 receptors usually increases intracellular cAMP levels through activation of G s protein, 12 resulting in a decrease of intracellular Ca 2ϩ levels. Human platelets contain mRNA for EP1 receptors,...
Accumulation of type 2 T helper (Th2) lymphocytes and eosinophils is a hallmark of bronchial asthma and other allergic diseases, and it is believed that these cells play a crucial pathogenic role in allergic inflammation. Thus, Th2 cells and eosinophils are currently considered a major therapeutic target in allergic diseases and asthma. However, drugs that selectively target the accumulation and activation of Th2 cells and eosinophils in tissues are unavailable so far. Prostaglandin (PG)D2 is a key mediator in various inflammatory diseases including allergy and asthma. It is generated by activated mast cells after allergen exposure and subsequently orchestrates the recruitment of inflammatory cells to the tissue. PGD2 induces the chemotaxis of Th2 cells, basophils and eosinophils, stimulates cytokine release from these cells and prolongs their survival, and might hence indirectly promote IgE production. PGD2 mediates its biologic functions via 2 distinct G protein-coupled receptors, D-type prostanoid receptor (DP), and the chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). DP and CRTH2 receptors are currently being considered as highly promising therapeutic targets for combating allergic diseases and asthma. Here, we revisit the roles of PGD2 receptors in the regulation of eosinophil and Th2 cell function and the efforts towards developing candidate compounds for clinical evaluation.
Accumulation of eosinophils in tissue is a hallmark of allergic inflammation. Here we observed that a selective agonist of the PGE2 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 Ca2+ mobilization. The involvement of the EP4 receptor was substantiated by a selective EP4 antagonist, which reversed the inhibitory effects of PGE2 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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00018-011-0642-5) contains supplementary material, which is available to authorized users.
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