Rapid Selective Priming of FcαR 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 FcαR (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 FcαR, eosinophil FcγRII (CD32) was not affected by Dex. Further characterization of the Dex-induced inside-out regulation of FcαR 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 FcαR. This work demonstrates that corticosteroids selectively activate the FcαR on eosinophils by activation of p38 MAPK.

T Cell Receptor Signaling Can Directly Enhance the Avidity of CD28 Ligand Binding

“…Cytokine signaling has been shown to enhance ligand binding to the IgA and IgG Fc receptors [40], [41]. The signaling pathways that mediate this effect have been identified [42], [43], but the changes to the extracellular domains to allow for enhanced ligand binding remain unknown. Interesting for CEACAM1 [44], interactions between GXXXG transmembrane motifs appears to stabilize cis-dimers in the inactive form.…”

Steroids induce a disequilibrium of secreted interleukin-1 receptor antagonist and interleukin-1β synthesis by human neutrophils

“…Recent work has demonstrated that GCS are able to induce proinflammatory responses in these cells [20][21][22][23][24][25][26]. We tested the hypothesis that GCS affect TNF-a-induced synthesis and secretion of pro-and anti-inflammatory cytokines by neutrophils.…”

“…However, despite the strong capacity of GCS to inhibit inflammation, inhibition of neutrophil-driven inflammation seems to be less effective [19]. Other studies have shown that GCSs elicit proinflammatory effects on granulocytes, such as increased interleukin (IL)-1 receptor (IL-1R) type I expression on human neutrophils [20], prolonged neutrophil survival in vitro [21,22], leukocytosis in vivo [23], p38 activation in neutrophils and eosinophils [24,25], increased immunoglobulin A binding by eosinophils [25], and increased secretion of lysosomal enzymes by neutrophils [26]. Because not only proinflammatory, but also anti-inflammatory, mediators are controlled by the transcription factor NF-kB, GCSs would be expected to affect the expression of anti-inflammatory response as well, which is not often assessed.…”

Elevated Membrane and Soluble CD64: A Novel Marker Reflecting Altered FcγR Function and Disease in Early Rheumatoid Arthritis That Can Be Regulated by Anti-Rheumatic Treatment

“…The supernatants were analyzed in an anti-TNFα ELISA as described [ 31 , 42 ]. Briefly, microtiter plates were coated with mouse anti-human TNFα capture ab (2 μg/ml) (MAB610/clone 28401; R&D Systems, USA) overnight in a humid chamber.…”