Prostaglandin D2 is a potent chemoattractant for human eosinophils that acts via a novel DP receptor.
Prostaglandin D2 (PGD2) is released following exposure of asthmatics to allergen and acts via the adenylyl cyclase-coupled receptor for PGD2 (DP receptor). In this study, it is reported that human eosinophils possess this receptor, which would be expected to inhibit their activation. In contrast, it was found that prostaglandin D2 is a potent stimulator of eosinophil chemotaxis, actin polymerization, CD11b expression, and L-selectin shedding. These responses are specific for eosinophils, as neutrophils display little or no response to prostaglandin D2. They were not due to interaction with receptors for other prostanoids, as prostaglandins E2 and F(2alpha), U46619 (a thromboxane A2 analogue), and carbaprostacyclin (a prostacyclin analogue) displayed little or no activity. Furthermore, they were not shared by the selective DP receptor agonist BW245C and were not prevented by the selective DP receptor antagonist BWA868C, indicating that they were not mediated by DP receptors. In contrast, the prostaglandin D2 metabolite 13,14-dihydro-15-oxoprostaglandin D2 induced eosinophil activation but did not stimulate DP receptor-mediated adenosine 3',5'-cyclic monophosphate (cAMP) formation. These results indicate that in addition to the classic inhibitory DP1 receptor, eosinophils possess a second, novel DP2 receptor that is associated with PGD2-induced cell activation. These 2 receptors appear to interact to regulate eosinophil responses to PGD2, as blockade of DP1 receptor-mediated cAMP production by BWA868C resulted in enhanced DP2 receptor-mediated stimulation of CD11b expression. The balance between DP1 and DP2 receptors could determine the degree to which prostaglandin D2 can activate eosinophils and may play a role in eosinophil recruitment in asthma.
Monneret
G
G
Meakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, QC, Canada.
Gravel
S
S
Diamond
M
M
Rokach
J
J
Powell
W S
WS
D000199:Actins / Q000378:metabolism; D002478:Cells, Cultured; D002630:Chemotactic Factors / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte; D000242:Cyclic AMP / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004804:Eosinophils / Q000276:immunology*; D006801:Humans; D006827:Hydantoins / Q000494:pharmacology; D019041:L-Selectin / Q000378:metabolism; D016177:Macrophage-1 Antigen / Q000096:biosynthesis; D008954:Models, Biological; D009504:Neutrophils / Q000276:immunology; D015230:Prostaglandin D2 / Q000494:pharmacology*; D011453:Prostaglandins / Q000494:pharmacology; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000199:Actins; D002630:Chemotactic Factors; D006827:Hydantoins; D016177:Macrophage-1 Antigen; D011453:Prostaglandins; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; C058848:BW A868C; D019041:L-Selectin; D000242:Cyclic AMP; D015230:Prostaglandin D2; C036293:prostaglandin D2 receptor