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Rapid Selective Priming of FcR on Eosinophils by Corticosteroids

Willem ten Hove^*,, Leo A. Houben^*, Jan A. M. Raaijmakers, Leo Koenderman^1,2,* and Madelon Bracke^2,*,

^* Department of Pulmonary Diseases, University Medical Center Utrecht, Utrecht, The Netherlands; and Department of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute of Pharmaceutical Sciences, Utrecht, The Netherlands

Preactivation or priming of eosinophils by (proinflammatory) cytokines is important in the pathogenesis of allergic diseases. Several priming-dependent eosinophil responses, such as migration and adhesion, are reduced by treatment with corticosteroids. Many inhibitory effects of corticosteroids are mediated by the glucocorticoid receptor via genomic mechanisms, which are evident only after prolonged interaction (>30 min). However, also faster actions of corticosteroids have been identified, which occur in a rapid, nongenomic manner. In this study, fast effects of corticosteroids were investigated on the function of eosinophil opsonin receptors. Short term corticosteroid treatment of eosinophils for maximal 30 min with dexamethasone (Dex) did not influence eosinophil cell surface CD11b/CD18 expression, adhesion, and/or chemokinesis. In marked contrast, incubation with Dex resulted in a rapid increase in binding of IgA-coated beads to human eosinophils, showing that Dex can up-regulate the activation of FcR (CD89). This priming response by Dex was dose dependent and optimal between 10^–8 and 10^–6 M and was mediated via the glucocorticoid receptor as its selective antagonist RU38486 (10^–6 M) blocked the priming effect. In contrast to FcR, eosinophil FcRII (CD32) was not affected by Dex. Further characterization of the Dex-induced inside-out regulation of FcR revealed p38 MAPK as the central mediator. Dex dose dependently enhanced p38 MAPK phosphorylation and activation in situ as measured by phosphorylation of its downstream target mitogen-activated protein kinase-activated protein kinase 2. The dose responses of the Dex-induced activation of these kinases were similar as seen for the priming of FcR. This work demonstrates that corticosteroids selectively activate the FcR on eosinophils by activation of p38 MAPK.

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 Address correspondence and reprint requests to Dr. Leo Koenderman, Department of Pulmonary Diseases, University Medical Center, hpn. H.02.128, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. E-mail address: L.Koenderman{at}umcutrecht.nl

² Authors contributed equally to this article.

³ Abbreviations used in this paper: ICS, inhaled corticosteroids; Dex, dexamethasone; GCR, glucocorticoid receptor; HSA, human serum albumin; MAPKAP-K2, mitogen-activated protein kinase-activated protein kinase 2.