Agonist and antagonist effects of 15R-prostaglandin (PG) D2 and 11-methylene-PGD2 on human eosinophils and basophils.
Prostaglandin (PG) D2 acts through both the DP(1) 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 approximately 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, approximately 2 microM). 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.
Cossette
Chantal
C
Meakins-Christie Laboratories, Department of Medicine, McGill University, 3626 St. Urbain Street, Montreal, Quebec H2X 2P2, Canada.
Walsh
Sinead E
SE
Kim
Seongjin
S
Lee
Gue-Jae
GJ
Lawson
John A
JA
Bellone
Sophie
S
Rokach
Joshua
J
Powell
William S
WS
D000199:Actins / Q000737:chemistry; D001491:Basophils / Q000187:drug effects* / Q000502:physiology; D039481:CD11b Antigen / Q000032:analysis; D002465:Cell Movement / Q000187:drug effects; D000242:Cyclic AMP / Q000096:biosynthesis; D004804:Eosinophils / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology*; D011971:Receptors, Immunologic / Q000819:agonists / Q000037:antagonists & inhibitors / Q000187:drug effects*; D011982:Receptors, Prostaglandin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000187:drug effects*; D013237:Stereoisomerism
C516972:11-methyleneprostaglandin D2; D000199:Actins; D039481:CD11b Antigen; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; C470438:15-methylprostaglandin D2; D000242:Cyclic AMP; D015230:Prostaglandin D2; C036293:prostaglandin D2 receptor