15R-Methyl-Prostaglandin D₂Is a Potent and Selective CRTH2/DP₂Receptor Agonist in Human Eosinophils

Abstract

Prostaglandin D 2 (PGD 2 ) is a mast cell-derived mediator that seems to play a role in asthma and allergic diseases. It is the only primary prostanoid to activate human eosinophils, which it accomplishes through the DP 2 receptor/chemoattractant receptor-homologous molecule expressed on T helper cell type 2 (Th2) cells (CRTH2). In addition, PGD 2 has both pro-and antiinflammatory effects via the adenylyl cyclase-coupled DP 1 receptor. To attempt to identify potent and selective DP 2 receptor agonists we compared the abilities of a series of PGD 2 analogs to activate eosinophils via the DP 2 receptor with their abilities to stimulate adenylyl cyclase in platelets via the DP 1 receptor. All of the PGD 2 analogs tested stimulated CD11b expression and actin polymerization with a rank order of potency of 15R-methyl-PGD 2 Ͼ PGD 2 Ͼ 17-phenyl-18,19,20-trinor-PGD 2 Ͼ 15S-methyl-PGD 2 Ϸ 16,16-dimethyl-PGD 2 Ͼ 11-keto-fluprostenol. Surprisingly, 15R-methyl-PGD 2 , which has the unnatural R-configuration at carbon 15, was about 5 times more potent than PGD 2 and about 75 times more potent than 15S-methyl-PGD 2 . 15R-methyl-PGD 2 (EC 50 value of 1.7 nM) was also much more potent as an eosinophil chemoattractant than PGD 2 (EC 50 value of 10 nM) and 15S-methyl-PGD 2 (EC 50 value of 128 nM). Cross-desensitization experiments indicated that 15R-methyl-PGD 2 acts through the DP 2 receptor. None of the PGD 2 analogs tested elevated platelet cAMP by more than 20% of the maximal level in response to PGD 2 . However, in contrast to eosinophils, the most active was 15S-methyl-PGD 2 .In conclusion, 15R-methyl-PGD 2 is the most potent known DP 2 receptor agonist, and because of its selectivity and resistance to metabolism, should be a useful tool in probing the physiological role of this receptor in inflammatory diseases.

Evidence for a Second Receptor for Prostacyclin on Human Airway Epithelial Cells That Mediates Inhibition of CXCL9 and CXCL10 Release

“…Fourth, the activity of naturally occurring prostanoids at their cognate receptors requires a hydroxyl-bearing chiral center at position C15 that, typically, is in the S configuration ( Fig. 1; Monneret et al, 2003). The potent activity of 15R-TIC and 15-deoxy-TIC, therefore, is difficult to explain unless 1) the 15S-configuration is not critical for IP receptor agonism [as has been shown for DP 2 receptor activation (Monneret et al, 2003) In the present study, using a panel of IP receptor agonists (PGI 2 , iloprost, taprostene, 15-deoxy-TIC; Fig.…”

“…1; Monneret et al, 2003). The potent activity of 15R-TIC and 15-deoxy-TIC, therefore, is difficult to explain unless 1) the 15S-configuration is not critical for IP receptor agonism [as has been shown for DP 2 receptor activation (Monneret et al, 2003) In the present study, using a panel of IP receptor agonists (PGI 2 , iloprost, taprostene, 15-deoxy-TIC; Fig. 1) and the surmountable, competitive, and selective IP receptor antag- (Bley et al, 2006), we now provide clear functional evidence for the coexpression of two IP receptor subtypes on the human airway epithelial cell line, BEAS-2B, that mediate distinct functional responses.…”

Cutting Edge: Chemoattractant Receptor-Homologous Molecule Expressed on TH2 Cells Plays a Restricting Role on IL-5 Production and Eosinophil Recruitment

“…Ϫ/Ϫ mice PGD 2 was shown to be a chemoattractant for eosinophils in vitro (2) and CRTH2 selective analogues of PGD 2 that has CRTH2 agonist activity were shown to attract eosinophils in vivo (10,12). Because the broader spectrum selectivity is unclear for these agonist compounds, CRTH2 Ϫ/Ϫ mice would provide an ideal tool to examine the role in CRTH2 in eosinophil migration.…”

“…Thus, in wild-type mice, CRTH2 controls eosinophil recruitment through limitation of IL-5 production. This finding is surprising, because CRTH2 was thought to mediate the chemotactic effect of PGD 2 on eosinophils (10,12).…”

Agonist and Antagonist Effects of 15R-Prostaglandin (PG) D2and 11-Methylene-PGD2on Human Eosinophils and Basophils

“…We recently identified 15R-methyl-PGD 2 as the most potent DP 2 receptor agonist yet reported (Monneret et al, 2003). This compound is about 5 times more potent than PGD 2 and about 75 times more potent than 15S-methyl-PGD 2 , which bears the natural S configuration at C 15 .…”