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INFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

Agonist and Antagonist Effects of 15R-Prostaglandin (PG) D₂ and 11-Methylene-PGD₂ on Human Eosinophils and Basophils

Meakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, Quebec, Canada (C.C., S.E.W., W.S.P.); Claude Pepper Institute and Department of Chemistry, Florida Institute of Technology, Melbourne, Florida (S.K., G.-J.L., S.B., J.R.); and the Center for Experimental Therapeutics, University of Pennsylvania, Philadelphia, Pennsylvania (J.A.L.)

Prostaglandin (PG) D₂ acts through both the DP₁ receptor, which is coupled to adenylyl cyclase, and the DP₂ receptor (chemoattractant receptor-homologous molecule expressed on Th2 cells), 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 of 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-hydroxyl 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.

Address correspondence to: Dr. William S. Powell, Meakins-Christie Laboratories, McGill University, 3626 St. Urbain Street, Montreal, Quebec H2X 2P2, Canada. E-mail: William.Powell{at}McGill.ca