Glucocorticoids inhibit eosinophil responses to granulocyte-macrophage colony-stimulating factor.
The role of the eosinophil as an active proinflammatory cell in asthma and other allergic disorders has been well established. Glucocorticosteroids have long been used therapeutically as antiinflammatory agents in a variety of disease states where eosinophilia is a prominent feature. Although glucocorticoids are known to reduce tissue and circulating eosinophil numbers, the mechanisms by which they do so have not been clearly elucidated. Culture of eosinophils in vascular endothelial cell supernatants (VEC SUP) induces phenotypic and functional changes and prolongs the survival of the eosinophils. The survival-promoting activity in VEC SUP was shown to be granulocyte-macrophage CSF (GM-CSF) by neutralization with specific antibody. The potent glucocorticosteroid, dexamethasone (DEX), inhibited the prolongation of eosinophil survival caused by culture in either VEC SUP or human rGM-CSF. DEX (10(-6) M) exerted a direct survival-inhibitory effect on the eosinophil by the 4th day in culture in VEC SUP. This survival-inhibitory effect was dependent on the concentration of DEX (10(-10)-10(-6) M). Other glucocorticoids, including prednisolone (10(-7), 10(-6) M) and hydrocortisone (10(-7), 10(-6) M) also inhibited survival. The rank order of potency of the steroids indicates that this effect is mediated by a glucocorticoid receptor. This conclusion is supported by the failure of the sex steroids testosterone (10(-8)-10(-6) M) or beta-estradiol (10(-6) M) to inhibit eosinophil survival in the presence of VEC SUP. The effect of glucocorticoids on eosinophils is not a simple direct toxic effect because it was reversed by higher concentrations of GM-CSF. DEX shifted the GM-CSF dose-response curve for survival approximately fivefold to the right. GM-CSF induced a shift in eosinophil buoyant density which was partially blocked by DEX. These results suggest that glucocorticoids may inhibit elements of cytokine "priming" of eosinophils and that the eosinophilopenic effects of glucocorticoids may result in part from a direct effect on the eosinophil within a regulatory system involving cytokines.
Lamas
A M
AM
University of Miami School of Medicine, Department of Medicine, FL 33101.
Leon
O G
OG
Schleimer
R P
RP
D002470:Cell Survival / Q000187:drug effects; D002499:Centrifugation, Density Gradient; D003907:Dexamethasone / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000502:physiology; D004804:Eosinophils / Q000166:cytology / Q000187:drug effects*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques
D003907:Dexamethasone; D016178:Granulocyte-Macrophage Colony-Stimulating Factor