Endothelium-derived prostaglandin I2 controls the migration of eosinophils

BackgroundEnhanced eosinophil migration from the blood into the tissue is a hallmark of allergic diseases. Prostaglandin (PG) I2 is the major prostanoid released by endothelial cells. Mice deficient in PGI2 receptors (IPs) show exaggerated eosinophilic inflammation in response to allergen.ObjectiveWe set out to determine the role of PGI2 in eosinophil trafficking.MethodsHuman lung microvascular endothelial cells and purified human eosinophils were used to study adhesion and transendothelial migration. Morphologic studies were performed with fluorescence microscopy.ResultsPGI2 markedly attenuated the migration of eosinophils through cell-free filters but had no effect on neutrophil migration. The inhibitory effect of PGI2 on eosinophils was prevented by the IP antagonist Cay10441 and the adenylyl cyclase inhibitor SQ22536. Similarly, PGI2 prevented the adhesion of eosinophils to fibronectin and the rapid upregulation and activation of the adhesion molecule CD11b. IP expression on eosinophils was confirmed by means of flow cytometry and Western blotting. Furthermore, when endothelial cells were treated with the COX inhibitor diclofenac to abolish PGI2 production, adhesion of eosinophils to endothelial monolayers and subsequent transendothelial migration were markedly enhanced. Similarly, the IP antagonist enhanced eosinophil adhesion to endothelial cells. Inhibition of PGI2 biosynthesis decreased the electrical resistance of endothelial monolayers and compromised the texture of adherent junctions, as visualized by means of VE-cadherin and F-actin staining.ConclusionWe propose that endothelium-derived PGI2 might be fundamental for the maintenance of the endothelial barrier function against infiltrating cells. These results suggest that selective IP agonists might have beneficial effects in allergic inflammation.