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Prostaglandin E₂ Inhibits Eosinophil Trafficking through E-Prostanoid 2 Receptors¹

Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria

The accumulation of eosinophils in lung tissue is a hallmark of asthma, and it is believed that eosinophils play a crucial pathogenic role in allergic inflammation. Prostaglandin (PG) E₂ exerts anti-inflammatory and bronchoprotective mechanisms in asthma, but the underlying mechanisms have remained unclear. In this study we show that PGE₂ potently inhibits the chemotaxis of purified human eosinophils toward eotaxin, PGD₂, and C5a. Activated monocytes similarly attenuated eosinophil migration, and this was reversed after pretreatment of the monocytes with a cyclooxygenase inhibitor. The selective E-prostanoid (EP) 2 receptor agonist butaprost mimicked the inhibitory effect of PGE₂ on eosinophil migration, whereas an EP2 antagonist completely prevented this effect. Butaprost, and also PGE₂, inhibited the C5a-induced degranulation of eosinophils. Moreover, selective kinase inhibitors revealed that the inhibitory effect of PGE₂ on eosinophil migration depended upon activation of PI3K and protein kinase C, but not cAMP. In animal models, the EP2 agonist butaprost inhibited the rapid mobilization of eosinophils from bone marrow of the in situ perfused guinea pig hind limb and prevented the allergen-induced bronchial accumulation of eosinophils in OVA-sensitized mice. Immunostaining showed that human eosinophils express EP2 receptors and that EP2 receptor expression in the murine lungs is prominent in airway epithelium and, after allergen challenge, in peribronchial infiltrating leukocytes. In summary, these data show that EP2 receptor agonists potently inhibit eosinophil trafficking and activation and might hence be a useful therapeutic option in eosinophilic diseases.

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 10934 and 11967 and the Austrian Science Fund (FWF) Grant P19424-B05 V.K. is funded by the Ph.D. Program Molecular Medicine of the Medical University of Graz, Graz, Austria.

² E.M.S. and P.S. contributed equally to the study.

³ Address correspondence and reprint requests to Dr. Akos Heinemann, Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitätsplatz 4, A-8010 Graz, Austria. E-mail address: akos.heinemann{at}meduni-graz.at

⁴ Abbreviations used in this paper: COX, cyclooxygenase; BAL, bronchoalveolar lavage; CRTH2, chemoattractant receptor homologous molecules of Th2 cells; DM, demethylated; EP, E-prostanoid; EPO, eosinophil peroxidase; PG, prostaglandin; PKA, protein kinase A; PKC, protein kinase C.

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