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Receptors Trafficking Through E-Prostanoid 2 Inhibits Eosinophil 2 Prostaglandin E2 Inhibits Eosinophil Trafficking through E-Prostanoid 2 Receptors This information is current as Eva M. Sturm, Petra Schratl, Rufina Schuligoi, Viktoria of October 2, 2021. Konya, Gunter J. Sturm, Irmgard Th. Lippe, Bernhard A. Peskar and Akos Heinemann J Immunol 2008; 181:7273-7283; ; doi: 10.4049/jimmunol.181.10.7273 http://www.jimmunol.org/content/181/10/7273 Downloaded from References This article cites 65 articles, 24 of which you can access for free at: http://www.jimmunol.org/content/181/10/7273.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on October 2, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2008 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Prostaglandin E2 Inhibits Eosinophil Trafficking through E-Prostanoid 2 Receptors1 Eva M. Sturm,2 Petra Schratl,2 Rufina Schuligoi, Viktoria Konya, Gunter J. Sturm, Irmgard Th. Lippe, Bernhard A. Peskar, and Akos Heinemann3 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 mecha- nisms 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 degran- Downloaded from ulation of eosinophils. Moreover, selective kinase inhibitors revealed that the inhibitory effect of PGE2 on eosinophil mi- gration 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 http://www.jimmunol.org/ agonists potently inhibit eosinophil trafficking and activation and might hence be a useful therapeutic option in eosinophilic diseases. The Journal of Immunology, 2008, 181: 7273–7283. osinophils are important effector cells in allergic dis- vating factor are also potent chemoattractants for eosinophils eases, particularly in late-phase reactions, because they (9–11). Lately, a cyclooxygenase (COX)-derived4 mediator of release bronchoconstrictor mediators such as leukotri- activated mast cells, prostaglandin (PG) D , and several of its E 2 ene C4 and other chemoattractants that cause further influx of metabolites have been revealed to potently stimulate eosinophil inflammatory cells into the tissue (1). Eosinophils produce chemotaxis (12, 13). proinflammatory cytokines and growth factors, including im- by guest on October 2, 2021 PGE2 is the predominant cyclooxygenase product of airway munoregulatory Th2-type cytokines (2–4). Mucosal damage in macrophages, epithelial cells, and smooth muscle cells and is asthma is associated with cytotoxic mediators that are released regarded as a potent inflammatory mediator due to its effects on by activated eosinophils, and it has been shown that asthmatic vasodilatation, vascular permeability, and nociception; how- patients who received treatment based on eosinophil counts in ever, the role of PGE in allergic inflammation is unclear. In the sputum had significantly fewer severe asthma exacerbations 2 asthmatic lung, PGE affects both airway smooth muscle and than patients treated according to standard management therapy 2 the inflammatory process; PGE causes bronchial relaxation (5). Moreover, animal studies have also shown that genetically 2 (14) and inhibits allergen induced bronchoconstriction (15), but modified mice lacking eosinophils are protected against aller- it may also provoke bronchoconstrictor responses in some in- gen-induced lung injury and asthma (6, 7). A wide range of agonists can stimulate the accumulation of dividuals (16) because of activation of C fibers and reflex cho- eosinophils, in particular those of the CC chemokine family, linergic pathways (17). Moreover, PGE2 can induce cough di- which are acting through the chemokine receptor CCR3 (8). In rectly and sensitize the cough receptor (18). In humans and rats, addition, activated complement factors such as C5a, leukotri- PGE2 reduces allergen-induced airway eosinophilia (19, 20), enes, 5-oxo-6,8,11,14-eicosatetraenoic acid, and platelet-acti- abrogates eosinophil accumulation after passive cutaneous ana- phylaxis in the guinea pig (21), and protects against bleomycin- induced pulmonary fibrosis in mice (22). Conversely, eosino- Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria phil influx is exaggerated in COX-1 or COX-2 knockout mice Received for publication July 7, 2008. Accepted for publication September 18, 2008. (23, 24) and also in mice treated with selective COX-1 or The costs of publication of this article were defrayed in part by the payment of page COX-2 inhibitors (25). Decreased airway mucosal PGE2 pro- charges. This article must therefore be hereby marked advertisement in accordance duction during airway obstruction has been found in equine with 18 U.S.C. Section 1734 solely to indicate this fact. 1 This work was supported by the Jubila¨umsfonds 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. 4 Abbreviations used in this paper: COX, cyclooxygenase; BAL, bronchoalveolar 2 lavage; CRTH2, chemoattractant receptor homologous molecules of Th2 cells; DM, E.M.S. and P.S. contributed equally to the study. demethylated; EP, E-prostanoid; EPO, eosinophil peroxidase; PG, prostaglandin; 3 Address correspondence and reprint requests to Dr. Akos Heinemann, Institute of PKA, protein kinase A; PKC, protein kinase C. Experimental and Clinical Pharmacology, Medical University of Graz, Universita¨- tsplatz 4, A-8010 Graz, Austria. E-mail address: [email protected] Copyright © 2008 by The American Association of Immunologists, Inc. 0022-1767/08/$2.00 www.jimmunol.org 7274 EP2 RECEPTORS AND EOSINOPHIL TRAFFICKING Table I. Compounds used in this study and their target selectivity glucose, 3.33 mM CaCl2, 4.56 mM KCl, 1.5 mM NaH2PO4, 0.7 mM Na2HPO4, and 0.49 mM MgCl2. Reference Preparation of human leukocytes Name Selectivitya Activity No. Blood was sampled from healthy volunteers according to a protocol AH-6809 EP2 ϭ EP1 Ͼ Antagonist 57 approved by the Ethics Committee of the Medical University of Graz DP ϭ EP3 (Graz, Austria). All volunteers provided informed consent. Blood sam- Butaprost EP2 Agonist 57 ples were processed as described previously (29, 30). In brief, platelet- Chelerythrine PKC Inhibitor 58 rich plasma was removed by centrifugation of citrated whole blood, Diclofenac COX-1 ϭ COX-2 Inhibitor 59 after which erythrocytes and platelets were removed by dextran sedi- H-89 PKA Inhibitor 60, 61 mentation. Preparations of polymorphonuclear leukocytes, containing LY-294002 PI3K Inhibitor 11 eosinophils and neutrophils, and PBMC, including monocytes, ba- ONO-AE-248 EP3 Agonist 62 sophils, and lymphocytes, were made by Histopaque gradients (31). For ONO-AE1–329 EP4 Agonist 63 chemotaxis, eosinophils were further purified from polymorphonuclear ONO-AE3–208 EP4 Antagonist 64 populations by negative magnetic selection using an Ab mixture (CD2, PMA PKC Activator 48 CD14, CD16, CD19, CD56, and glycophorin A) and colloidal magnetic SB-202190 P38 MAPK Inhibitor 11 particles from StemCell Technologies. Resulting populations of eosin- SC-51089 EP1 Antagonist 57 ophils were typically Ͼ97%, with the majority of contaminating cells SQ-22536 Adenylyl cyclase Inhibitor 60 being neutrophils. Staurosporine Protein kinases Inhibitor 65 Culture of human peripheral blood monocytes a DP is D-prostanoid receptor. PBMC were resuspended in RPMI 1640 supplemented with penicillin (100 U/ml), streptomycin (100 ␮g/ml), glutamine (20 mM), nonessential amino Downloaded from acids, HEPES (50 mM) and sodium pyruvate (10 mM) at 6.7 ϫ 106/ml. asthma (26). At the cellular level, PGE2 has been found to at- Aliquots
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