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Inhibitory effects of prostaglandin EP4 receptors on human eosinophils
BMC Pharmacology volume 9, Article number: A2 (2009)
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 broncho-protective mechanisms in asthma, but the underlying mechanisms have remained unclear. We have shown previously that PGE2 and the EP2 receptor agonist butaprost inhibit eosinophil trafficking in vitro and in vivo.
Human eosinophils were purified by negative magnetic selection from peripheral blood. Cell migration was determined in microBoyden chemotaxis chambers. Ca2+ flux and expression of cell surface markers was recorded by flow cytometry. EP4 receptor expression was demonstrated by immunostaining.
The chemotaxis of eosinophils towards eotaxin and C5a was attenuated by the EP4 agonist ONO-AE1-329, and the EP4 antagonists ONO-AE3-208 and GW627368x partially reversed the inhibitory effect of PGE2 on eosinophil migration. ONO-AE1-329, and also PGE2, but not butaprost, inhibited the Ca2+ flux and the production of reactive oxygen species in eosinophils. ONO-AE1-329 also inhibited eosinophil degranulation and the up-regulation of the adhesion molecule CD11b. Selective kinase inhibitors revealed that the inhibitory effect of EP4 stimulation on eosinophil migration depended upon activation of phosphatidylinositol 3-kinase and protein kinase C, but not cAMP. Immunostaining showed that human eosinophils express EP4 receptors and that EP4 receptor expression in the murine lungs is prominent in airway epithelium, and after allergen challenge, in peribronchial infiltrating leukocytes.
These data show that EP4 receptor agonists potently inhibit eosinophil trafficking and activation, and might hence be a useful therapeutic option in eosinophilic diseases.
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Luschnig-Schratl, P., Sturm, E.M., Kónya, V. et al. Inhibitory effects of prostaglandin EP4 receptors on human eosinophils. BMC Pharmacol 9 (Suppl 2), A2 (2009). https://doi.org/10.1186/1471-2210-9-S2-A2
- Human Eosinophil
- Eosinophil Migration
- Eosinophil Degranulation
- Molecule CD11b
- Selective Kinase Inhibitor