EP4 receptor stimulation down-regulates human eosinophil function

Luschnig-Schratl, Petra; Sturm, Eva; Kónya, Viktória; Philipose, Sonia; Marsche, Gunther; Frőhlich, Eleonore; Samberger, Claudia; Lang‐Loidolt, Doris; Gattenlöhner, Stefan; Lippe, Irmgard Th.; Peskar, Bernhard A.; Schuligoi, Rufina; Heinemann, Ákos

doi:10.1007/s00018-011-0642-5

Cited by 47 publications

(57 citation statements)

References 62 publications

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“…This effect was at least partially reversed by the EP4 antagonist [18], although EP2 receptors were also found to be involved in this setup. In further experiments, we could substantiate the inhibitory role of EP4 receptors in eosinophils in assays of CD11b upregulation, production of reactive oxygen species and Ca 21 mobilization [40]. These findings have now fundamentally been extended by the current study as we found that the regulatory role of EP4 receptors translates to preventing the interaction of eosinophils with the endothelium, which is probably the most crucial step in eosinophil recruitment to the sites of inflammation.…”

Section: Discussionsupporting

confidence: 65%

Interaction of eosinophils with endothelial cells is modulated by prostaglandin EP4 receptors

et al. 2011

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Eosinophil extravasation across the endothelium is a key feature of allergic inflammation. Here, we investigated the role of PGE 2 and its receptor, E-type prostanoid receptor (EP)-4, in the regulation of eosinophil interaction with human pulmonary microvascular endothelial cells. PGE 2 and the EP4 receptor agonist ONO AE1-329 significantly reduced eotaxininduced eosinophil adhesion to fibronectin, and formation of filamentous actin and gelsolin-rich adhesive structures. These inhibitory effects were reversed by a selective EP4 receptor antagonist, ONO AE3-208. PGE 2 and the EP4 agonist prevented the activation and cell-surface clustering of b2 integrins, and L-selectin shedding of eosinophils. Under physiological flow conditions, eosinophils that were treated with the EP4 agonist showed reduced adhesion to endothelial monolayers upon stimulation with eotaxin, as well as after TNF-a-induced activation of the endothelial cells. Selective activation of EP1, EP2, and EP3 receptors did not alter eosinophil adhesion to endothelial cells, whereas the EP4 antagonist prevented PGE 2 from decreasing eosinophil adhesion. Finally, eosinophil transmigration across thrombin-and TNF-a-activated endothelial cells was effectively reduced by the EP4 agonist. These data suggest that PGE 2 -EP4 signaling might be protective against allergic responses by inhibiting the interaction of eosinophils with the endothelium and might hence be a useful therapeutic option for controlling inappropriate eosinophil infiltration.Keywords: Adhesion . Endothelium . Eosinophils . Migration . Prostaglandins Supporting Information available online IntroductionEosinophil granulocytes are important effector cells in allergic inflammation and are recruited to the tissue by chemotactic signals [1][2][3][4][5]. The infiltrating eosinophils release several toxic and proinflammatory mediators which induce epithelial injury, airway hyper-responsiveness, and airway remodeling [6][7][8]. Therefore, eosinophils are regarded as potential therapeutic targets in allergic diseases and asthma [9].Prostaglandins (PGs) play diverse roles in inflammation, depending on the cellular context, the type of PG being released, and the differential expression of PG receptors [10,11]. While PGD 2, which is the predominant PG formed in mast cells, exerts proinflammatory effects by regulating the recruitment of eosino- Eur. J. Immunol. 2011. 41: 2379-2389 DOI 10.1002 Leukocyte signaling 2379 phils, basophils, and Th2 lymphocytes to the sites of allergic inflammation [12], PGE 2 seems to attenuate inflammatory responses and reduce tissue injury in airways [13]. PGE 2 was found to exert bronchoprotective effects in patients with asthma [14]. In rats, the ovalbumin-induced early and late phase airway responses were inhibited by intratracheally administered PGE 2 [15]. The activity of PGE 2 is mediated by four subtypes of E-type prostanoid receptors (EP), EP1, EP2, EP3, and EP4 [16]. These G protein-coupled receptors have distinct biological imprints depending on their affinity with...

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Section: Discussionsupporting

confidence: 65%

Interaction of eosinophils with endothelial cells is modulated by prostaglandin EP4 receptors

et al. 2011

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“…EP4 may inhibit migration and adhesion of eosinophils (Table 3). In human eosinophils, EP4 mRNA was highly expressed (Mita et al, 2002;Luschnig-Schratl et al, 2011). The selective EP4 agonist ONO-AE1-329 potently attenuated the chemotaxis of human peripheral blood eosinophils through the PI3K pathway, but not the cAMP pathway (LuschnigSchratl et al, 2011).…”

Section: Other Immune Cellsmentioning

confidence: 99%

The Prostanoid EP4 Receptor and Its Signaling Pathway

Yokoyama

Iwatsubo²,

Umemura³

et al. 2013

Pharmacol Rev

227

257

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“…Respiratory burst of leukocytes was quantified by oxidation of nonfluorescent 29-79-dichlorodihydrofluorescein to fluorescent 29-79-dichlorofluorescein in flow cytometry (18).…”

Section: Respiratory Burstmentioning

confidence: 99%

A Biased Non-Gαi OXE-R Antagonist Demonstrates That Gαi Protein Subunit Is Not Directly Involved in Neutrophil, Eosinophil, and Monocyte Activation by 5-Oxo-ETE

Kónya

Blättermann

Jandl

et al. 2014

The Journal of Immunology

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Gαi-coupled chemoattractant receptors, such as the 5-oxo-6E,8Z,11Z,14Z-eicosatetraenoic acid (5-oxo-ETE) receptor (OXE-R), are able to switch on Gαiβγ protein-dependent and β-arrestin–related signaling traits. However, which of these signaling pathways are truly important for the chemoattractant functions in leukocytes is not clarified yet. As we recently reported, Gue1654 is a unique Gβγ-biased OXE-R antagonist having no inhibitory activity on Gαi-related signaling, which makes Gue1654 an unprecedented tool for assessing the involvement of G protein subunits in chemoattractant receptor function. β-arrestin2 recruitment was studied in OXE-R–overexpressing HEK293 cells using bioluminescence resonance energy transfer assays. Activation of leukocytes was assessed by flow cytometric assays and by immunofluorescence microscopy. Leukocyte capture to endothelial cells was addressed under physiological flow conditions. We found that Gue1654 blocks β-arrestin2 recruitment in HEK293 cells overexpressing OXE-R and ERK1/2 phosphorylation in human eosinophils and neutrophils. Furthermore, Gue1654 was able to prevent several 5-oxo-ETE–triggered functional events in eosinophils and neutrophils, such as activation of CD11b/CD18 integrins, oxidative burst, actin polymerization, and interaction with endothelial cells. In addition, Gue1654 completely prevented 5-oxo-ETE–induced Ca2+ flux and chemotaxis of human primary monocytes. All of these leukocyte responses to 5-oxo-ETE, except ERK1/2 phosphorylation and oxidative burst, were likewise prevented by pertussis toxin. Therefore, we conclude that chemoattractant receptors require Gαi subunits only as adaptors to transactivate the Gβγ heteromers, which then act responsible for cell activation. Finally, our data characterize Gue1654 as a non-Gαi–biased antagonist of OXE-R that provides a new basis for therapeutic intervention in inflammatory diseases that involve activation of eosinophils, neutrophils, and monocytes.

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EP4 receptor stimulation down-regulates human eosinophil function

Cited by 47 publications

References 62 publications

Interaction of eosinophils with endothelial cells is modulated by prostaglandin EP4 receptors

Interaction of eosinophils with endothelial cells is modulated by prostaglandin EP4 receptors

The Prostanoid EP4 Receptor and Its Signaling Pathway

A Biased Non-Gαi OXE-R Antagonist Demonstrates That Gαi Protein Subunit Is Not Directly Involved in Neutrophil, Eosinophil, and Monocyte Activation by 5-Oxo-ETE

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