Abstract
Prostaglandin (PG) D2 is an arachidonic acid metabolite that is released by allergen-stimulated mast cells. It is a potent in vitro chemoattractant for human eosinophils, acting through the DP2 receptor/chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2). Furthermore, there is in vivo evidence that PGD2 contributes to allergen-induced pulmonary eosinophilia via its classic DP1 receptor. The PGD2-derived product 15-deoxy-Δ12,14-PGJ2 is widely used as a peroxisome proliferator-activated receptor γ agonist and has been shown to have anti-inflammatory properties. However, this substance can also activate eosinophils in vitro through the DP2 receptor. The objectives of the present study were to determine whether PGD2 and 15-deoxy-Δ12,14-PGJ2 can induce pulmonary eosinophilia, and, if so, to examine the abilities of selective DP1 and DP2 receptor agonists to induce this response. Brown Norway rats were treated by intratracheal instillation of PGs. Vehicle and 5-oxo-6,8,11,14-eicosatetraenoic acid were used as negative and positive controls, respectively. Lung eosinophils were identified by immunostaining of lung sections with an antibody to major basic protein. Both PGD2 and 15-deoxy-Δ12,14-PGJ2 induced robust eosinophilic responses that were apparent by 12 h and persisted for at least 48 h. Two selective DP2 receptor agonists, 15R-methyl-PGD2 and 13–14-dihydro-15-keto-PGD2, induced similar responses, the former being more potent than PGD2, whereas the latter was less potent. The selective DP1 receptor agonist BW245C [(4S)-(3-[(3R,S)-3-cyclohexyl-3-hydroxypropyl]-2,5-dioxo)-4-imidazolidineheptanoic acid] was completely inactive. We conclude that PGD2 and 15-deoxy-Δ12,14-PGJ2 induce eosinophil infiltration into the lungs through the DP2 receptor. The potent in vitro DP2 receptor agonist 15R-methyl-PGD2 is also very active in vivo and should be a useful tool in examining the role of this receptor.
Footnotes
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This study was supported by Canadian Institutes of Health Research Grants MOP-6254 (to W.S.P.), MOP-13273 (to Q.H.), and MOP-10381 (to J.G.M.); the J. T. Costello Memorial Research Fund; and National Institutes of Health Grants DK44730 and HL69835 (to J.R.). J.R. also acknowledges the National Science Foundation for an AMX-360 NMR instrument Grant CHE-90-13145.
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doi:10.1124/jpet.104.079079.
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ABBREVIATIONS: PG, prostaglandin; Th2, T helper 2; CRTH2, chemoattractant receptor-homologous molecule expressed on Th2 cells; dhk-PGD2, 13,14-dihydro-15-ketoprostaglandin D2; 15d-PGJ2, 15-deoxy-Δ12,14-prostaglandin J2; PPARγ, peroxisome proliferator activated receptor γ; 5-oxo-ETE, 5-oxo-6,8,11,14-eicosatetraenoic acid; BW245C, (4S)-(3-[(3R,S)-3-cyclohexyl-3-hydroxypropyl]-2,5-dioxo)-4-imidazolidineheptanoic acid; MBP, major basic protein; MDC, macrophage-derived chemokine (CCL22).
- Received October 14, 2004.
- Accepted December 6, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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