title: Rapid selective priming of FcalphaR on eosinophils by corticosteroids.
abstract: 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 FcalphaR (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 FcalphaR, eosinophil FcgammaRII (CD32) was not affected by Dex. Further characterization of the Dex-induced inside-out regulation of FcalphaR 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 FcalphaR. This work demonstrates that corticosteroids selectively activate the FcalphaR on eosinophils by activation of p38 MAPK.
authors.affiliation: Department of Pulmonary Diseases, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
authors.forename: Willem
authors.initials: W
authors.lastname: ten Hove
authors.forename: Leo A
authors.initials: LA
authors.lastname: Houben
authors.forename: Jan A M
authors.initials: JA
authors.lastname: Raaijmakers
authors.forename: Leo
authors.initials: L
authors.lastname: Koenderman
authors.forename: Madelon
authors.initials: M
authors.lastname: Bracke
mesh_terms: D000305:Adrenal Cortex Hormones / Q000494:pharmacology; D015703:Antigens, CD / Q000378:metabolism*; D039481:CD11b Antigen / Q000032:analysis; D018821:CD18 Antigens / Q000032:analysis; D002448:Cell Adhesion / Q000187:drug effects; D018925:Chemokines / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D004804:Eosinophils / Q000737:chemistry / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D018928:Immunity, Mucosal / Q000187:drug effects; D016023:Integrins / Q000032:analysis; D015735:Mifepristone / Q000494:pharmacology; D010088:Oxidoreductases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011961:Receptors, Fc / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000305:Adrenal Cortex Hormones; D015703:Antigens, CD; D039481:CD11b Antigen; D018821:CD18 Antigens; D018925:Chemokines; C036832:Fc(alpha) receptor; D016023:Integrins; D011961:Receptors, Fc; D015735:Mifepristone; D003907:Dexamethasone; D010088:Oxidoreductases; C431912:glutathione conjugate reductase; D019869:Phosphatidylinositol 3-Kinases; D048051:p38 Mitogen-Activated Protein Kinases