Received for publication July 28, 2006.
Revised October 4, 2006.
Accepted for publication October 11, 2006.

Agonist and antagonist effects of 15R-prostaglandin D₂ and 11-methylene-PGD₂ on human eosinophils and basophils

Abstract

Prostaglandin (PG) D₂ acts through both the DP₁ receptor, which is coupled to adenylyl cyclase, and the DP₂ receptor (CRTH2), which is present on eosinophils, basophils, and Th2 cells and results in cell activation and migration. The most potent prostanoid DP₂ agonist so far reported is 15R-methyl-PGD₂, in which the hydroxyl group has the unnatural R configuration. In contrast, the corresponding analog possessing the natural 15S configuration is ~75 times less potent. This raised the question whether the isoprostane 15R-PGD₂ might have potent DP₂ receptor-mediated biological activity. We therefore chemically synthesized 15R-PGD₂ and investigated its biological activity. This compound elicited DP₂ receptor-mediated CD11b expression in human basophils and eosinophils, and induced actin polymerization and migration in eosinophils with a potency about the same as that of PGD₂. In contrast, it had only a weak effect on DP₁ receptor-mediated adenylyl cyclase activity in human platelets. We also investigated the effects of modification of the 9-hydroxy and 11-oxo groups of PGD₂. Both PGK₂, in which the 9-hydroxyl group is replaced by an oxo group, and 11-deoxy-11-methylene PGD₂, in which the 11-oxo group is replaced by a CH₂ group, have little or no DP₁ or DP₂ agonist activity. However, the 11-methylene analog is a DP₂ antagonist (IC₅₀, ~2 µM). We conclude that 15R-PGD₂, which may be generated by oxidative stress, is a potent and selective DP₂ agonist and that modification of the 11-oxo group of PGD₂ can result in DP₂ antagonist activity.

Key words: DP2 receptor, Eicosanoids, Eosinophils, Inflammation, Prostaglandin D2, Stereochemistry