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Research ArticleINFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

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

Chantal Cossette, Sinead E. Walsh, Seongjin Kim, Gue-Jae Lee, John A. Lawson, Sophie Bellone, Joshua Rokach and William S. Powell
Journal of Pharmacology and Experimental Therapeutics January 2007, 320 (1) 173-179; DOI: https://doi.org/10.1124/jpet.106.111062
Chantal Cossette
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Sinead E. Walsh
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Seongjin Kim
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Gue-Jae Lee
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John A. Lawson
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Sophie Bellone
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Joshua Rokach
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William S. Powell
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Abstract

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.

Footnotes

  • This work was supported by the Canadian Institutes of Health Research (Grant MOP-6254 to W.S.P.), by the J.T. Costello Memorial Research Fund, and by the National Institutes of Health (Grants HL81873 and HL69835 to J.R.). J.R. acknowledges the National Science Foundation for a Bruker 400 MHz NMR instrument (Grant CHE-03 42251).

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.106.111062.

  • ABBREVIATIONS: PG, prostaglandin; 11-CH2-PGD2, 11-methylene-PGD2; FITC, fluorescein isothiocyanate; PE, phycoerythrin; PBS, phosphate-buffered saline; BSA, bovine serum albumin.

    • Received July 25, 2006.
    • Accepted October 11, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 382 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 382, Issue 2
1 Aug 2022
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Research ArticleINFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

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

Chantal Cossette, Sinead E. Walsh, Seongjin Kim, Gue-Jae Lee, John A. Lawson, Sophie Bellone, Joshua Rokach and William S. Powell
Journal of Pharmacology and Experimental Therapeutics January 1, 2007, 320 (1) 173-179; DOI: https://doi.org/10.1124/jpet.106.111062

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Research ArticleINFLAMMATION, IMMUNOPHARMACOLOGY, AND ASTHMA

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

Chantal Cossette, Sinead E. Walsh, Seongjin Kim, Gue-Jae Lee, John A. Lawson, Sophie Bellone, Joshua Rokach and William S. Powell
Journal of Pharmacology and Experimental Therapeutics January 1, 2007, 320 (1) 173-179; DOI: https://doi.org/10.1124/jpet.106.111062
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