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The Role of the Prostaglandin D₂ Receptor, DP, in Eosinophil Trafficking¹

Petra Schratl^*, Julia F. Royer^*, Evi Kostenis, Trond Ulven, Eva M. Sturm^*, Maria Waldhoer^*, Gerald Hoefler, Rufina Schuligoi^*, Irmgard Th. Lippe^*, Bernhard A. Peskar^* and Akos Heinemann^2,*

^* Institute of Experimental and Clinical Pharmacology, and Institute of Pathology, Medical University Graz, Graz, Austria; Institute for Pharmaceutical Biology, Bonn, Germany; and Department of Chemistry, University of Southern Denmark, Odense M, Denmark

Prostaglandin (PG) D₂ is a major mast cell product that acts via two receptors, the D-type prostanoid (DP) and the chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) receptors. Whereas CRTH2 mediates the chemotaxis of eosinophils, basophils, and Th2 lymphocytes, the role of DP has remained unclear. We report in this study that, in addition to CRTH2, the DP receptor plays an important role in eosinophil trafficking. First, we investigated the release of eosinophils from bone marrow using the in situ perfused guinea pig hind limb preparation. PGD₂ induced the rapid release of eosinophils from bone marrow and this effect was inhibited by either the DP receptor antagonist BWA868c or the CRTH2 receptor antagonist ramatroban. In contrast, BWA868c did not inhibit the release of bone marrow eosinophils when this was induced by the CRTH2-selective agonist 13,14-dihydro-15-keto-PGD₂. In additional experiments, we isolated bone marrow eosinophils from the femoral cavity and found that these cells migrated toward PGD_2. We also observed that BWA868c inhibited this response to a similar extent as ramatroban. Finally, using immunohistochemistry we could demonstrate that eosinophils in human bone marrow specimens expressed DP and CRTH2 receptors at similar levels. Eosinophils isolated from human peripheral blood likewise expressed DP receptor protein but at lower levels than CRTH2. In agreement with this, the chemotaxis of human peripheral blood eosinophils was inhibited both by BWA868c and ramatroban. These findings suggest that DP receptors comediate with CRTH2 the mobilization of eosinophils from bone marrow and their chemotaxis, which might provide the rationale for DP antagonists in the treatment of allergic disease.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the Jubiläumsfonds of the Austrian National Bank Grants 10287, 10934, and 11967; the Austrian Science Fund Fonds zur Förderung der Wissenschaftlichen Forschung (FWF) Grants P16668-B05 and P19424-B05, and the Franz Lanyar Foundation Grants 288 and 315.

² Address correspondence and reprint requests to Dr. Akos Heinemann, Department of Experimental and Clinical Pharmacology, Medical University of Graz, Universitaetsplatz 4, A-8010 Graz, Austria. E-mail address: akos.heinemann{at}meduni-graz.at

³ Abbreviations used in this paper: PG, prostaglandin; DP, D-type prostanoid receptor; CRTH2, chemoattractant receptor-homologous molecule expressed on Th2 cells; DK-PGD₂, 13,14-dihydro-15-keto-PGD₂; 15-deoxy-PGJ₂, 15-deoxy-(12, 14)-PGJ₂; LTB₄, leukotriene B₄; PMNL, polymorphonuclear leukocytes; Th2, Th 2; TP, thromboxane receptor; TXB₂, thromboxane B₂.