RT Journal Article
SR Electronic
T1 Agonist and Antagonist Effects of 15<em>R</em>-Prostaglandin (PG) D<sub>2</sub> and 11-Methylene-PGD<sub>2</sub> on Human Eosinophils and Basophils
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 173
OP 179
DO 10.1124/jpet.106.111062
VO 320
IS 1
A1 Chantal Cossette
A1 Sinead E. Walsh
A1 Seongjin Kim
A1 Gue-Jae Lee
A1 John A. Lawson
A1 Sophie Bellone
A1 Joshua Rokach
A1 William S. Powell
YR 2007
UL http://jpet.aspetjournals.org/content/320/1/173.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics