Rapid Selective Priming Of FcαR On Eosinophils By Corticosteroids (original) (raw)
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Rapid selective priming of FcalphaR on eosinophils by corticosteroids
Journal of immunology (Baltimore, Md. : 1950), 2006
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-regu...
Glucocorticoids preferentially upregulate functional CXCR4 expression in eosinophils
Journal of Allergy and Clinical Immunology, 2000
Background: Chemokines play an important role in accumulation of eosinophils at allergic inflammatory sites. Systemic administration of glucocorticoids (GCCs) attenuates tissue eosinophilia. In vivo chemokine actions are regulated at levels of both ligand production and receptor expression. The inhibitory effects of GCCs on the production of eosinophilactive chemokines, such as eotaxin, have been well established. However, no data exist regarding the effects of GCCs on expression of chemokine receptors in eosinophils per se. Objective: The objective of this study was to investigate the regulation of chemokine receptor expression in eosinophils by GCCs. Methods: Chemokine receptor expression was analyzed by using flow cytometry and reverse transcriptase PCR. Intracellular Ca 2+ influx and chemotaxis were also analyzed. Results: Eosinophil CCR3 expression was slightly downregulated by 24-hour treatment with dexamethasone (DEX). On the other hand, DEX-treated eosinophils showed markedly increased CXCR4 expression (~6 fold) in a time-and dosedependent fashion. In contrast to eosinophils, CXCR4 expression in neutrophils was only marginally affected by DEX. In DEX-treated eosinophils, stromal cell-derived factor 1α, a natural ligand for CXCR4, induced a higher level of Ca 2+ influx and chemotaxis compared with untreated cells. Conclusion: GCCs upregulate the expression of CXCR4 in eosinophils but not in neutrophils. Because stromal cell-derived factor 1α may play a role in baseline trafficking of eosinophils into extravascular tissues rather than recruiting them directly to inflammatory sites, upregulation of CXCR4 by GCCs may mediate the antiallergic property of these drugs by sequestering eosinophils from the circulation to extravascular tissues.
Glucocorticoid regulation of human eosinophil gene expression
Journal of Steroid Biochemistry and Molecular Biology, 2003
Molecular analysis of steroid-regulated gene expression in freshly isolated human eosinophils is difficult due to the inherent high rate of spontaneous apoptosis and elevated levels of endogenous ribonucleases. To circumvent these limitations, we determined if the human eosinophilic cell line EoL-1 could serve as an in vitro model of glucocorticoid signaling. We found by optimizing growth conditions in low serum-containing media that dexamethasone (Dex) treatment of EoL-1 cells induced an apoptotic pathway that was inhibited by interleukin-5 (IL-5). Moreover, gene expression profiling using RNA from untreated EoL-1 cells and from freshly isolated human eosinophils identified 380 commonly expressed genes, including the eosinophil markers granule major basic protein, prostaglandin-endoperoxide synthase 1 and arachidonate 15-lipoxygenase. Expression profiling was performed using EoL-1 cells that had been treated with dexamethasone for 0, 4, 12, 24 and 48 h identifying 162 genes as differentially expressed. Two of the most highly upregulated genes based on expression profiling were the transcription factor Ets-2 and the MHC Class II genes (Q, R, and P). Expression of these genes in EoL-1 cells was shown to be dexamethasone-induced at the RNA and protein levels which is consistent with the known function of Ets-2 in controlling cell cycle progression and the role of MHC Class II antigens in mediating eosinophil functions.
Glucocorticoid receptors in normal human eosinophils: comparison with neutrophils
Journal of Allergy and Clinical Immunology, 1981
Saturation analysis with [3H]-dexamethasone was employed to measure glucocorticoid binding in pkjied preparations of human eosinophils and neutrophils. Eosinophils contained 10.8 + 1.3 x 10" high-a@@ receptor sites per cell, with a dissociation constant (Kd) of 15.3 +-0.6 nM dexamethasone. Cortisol was capable of competing with [3H]-dexamethasone in the binding reaction, whereas progesterone, estradiol, estriol, and testosterone were less effective. Saturable glucocorticoid binding in neutrophils had a Kd of 17.7 2 0.8 nh4 dexamethasone with II .I k 0.8 X IO3 sites per cell ana' displayed similar steroid spec$city. These data indicate that normal human eosinophils have glucocorticoid receptors with characteristics similar to those in neutrophils and that in these cells ligand-receptor interaction can occur at physiologic glucocorticoid concentrations. Furthermore, these results suggest that certain glucocorticoid effects on eosinophils and neutrophils may be mediated through spectjic receptors. (J ALLERGY CLIN IMUUNOL 68:212, 1981.) Glucocorticoids are steroid hormones with potent anti-inflammatory effects. For this reason they are used extensively in the treatment of allergic, inflammatory, and autoimmune disorders such as asthma, rheumatoid arthritis, systemic lupus erythematosus, ulcerative colitis, and many dermatologic diseases. Eosinophils and neutrophils, long known to be responsive to glucocorticoid hormones, play a prominent role in many of these inflammatory and hypersensitivity diseases. The generally accepted model of glucocorticoid action involves hormone binding to specific intracellular cytoplasmic proteins,
Clin Mol …, 2005
Background: TNF-alpha is an important mediator in allergy also for its effects on eosinophils. Methods: The effect of dexamethasone on TNF-alpha induced eosinophils survival, degranulation (ECP), cytokines release (IL-8, GM-CSF) and adhesion to VCAM-1, ICAM-1 and IgG coated wells (EPO release) were evaluated. Results: The drug inhibited IL-8 and GM-CSF production, but not viability, degranulation or adhesion in human peripheral blood eosinophils. Conclusion: These results indicate that part of the activity of glucocorticosteroids on eosinophils may be mediated by their ability to inhibit cytokine secretion that in turn is important for the perpetuation of the allergic inflammation.
Glucocorticoid-induced apoptosis in human eosinophils: mechanisms of action
Apoptosis : an international journal on programmed cell death, 2003
Prominent blood and tissue eosinophilia is clinically manifested in a number of inflammatory states, particularly in allergic diseases. Corticosteroids are the most effective anti-inflammatory drugs used in the treatment of eosinophilic disorders, including bronchial asthma. Their beneficial effects result, among others, from (i) the suppression of the synthesis and the effects of eosinophil survival factors, (ii) the direct induction of eosinophil apoptosis and (iii) the stimulation of their engulfment by professional phagocytic cells. Failure of steroids to propagate apoptotic signals and to promote eosinophil clearance may explain the corticoresistance observed in a proportion of asthmatic patients. Accordingly, studies on the intracellular mechanisms involved in eosinophil corticosensitivity and resistance may provide a valuable tool for identifying new and selective molecular targets to therapeutically resolve otherwise persistent eosinophilic inflammation. In this review, the ...
European Journal of Pharmacology, 1999
We have studied the effect of local and systemic treatment with dexamethasone for prevention of the pleural eosinophilia triggered by allergen in actively sensitised Wistar rats. Parallel changes in blood and marrow eosinophil numbers were assessed for comparison. The Ž. intrapleural i.pl. injection of ovalbumin into ovalbumin-sensitised animals led to a long-lasting pleural fluid eosinophilia which peaked from 24 to 72 h post-challenge. At these time points, there was a significant 2-to 3-fold increase in the blood eosinophil numbers, Ž whereas the bone marrow number of mature eosinophils remained unaltered. Systemic treatment with dexamethasone 0.05-0.5 mgrkg,. i.p. abolished the pleural and blood eosinophilia observed 24 and 48 h post-challenge, also causing a significant reduction in marrow eosinophil numbers. Despite being unable to alter blood and bone marrow eosinophil numbers, the local i.pl. administration of Ž. dexamethasone 2.5-10 mgrcavity inhibited dose dependently the allergen-induced pleural eosinophil influx at 24 h but not at 48 h post-challenge. This treatment also shortened the time course of eosinophil accumulation in the pleural space from the 48 h time point on. We conclude that the effect of systemic but not of local treatment with dexamethasone on allergen-induced eosinophil recruitment is well correlated with the inhibition of eosinophil production in bone marrow. In contrast, low amounts of dexamethasone injected into the pleural space seem to affect locally eosinophil recruitment and survival.