Opposing effects of glucocorticoids on the rate of apoptosis in neutrophilic and eosinophilic granulocytes

Abstract

Eosinophils and neutrophils are closely related, terminally differentiated cells that in vitro undergo constitutive cell death by apoptosis. The onset of apoptosis in both cell types can be delayed by hemopoietins and inflammatory mediators. Although there have been a number of reports demonstrating that glucocorticoids (in particular dexamethasone) antagonize the eosinophil life-prolonging effects of hemopoietins, direct effects of dexamethasone on eosinophil apoptosis have not been documented. In this study we examined the direct effects of glucocorticoids on eosinophil and neutrophil apoptosis in light of their common therapeutic use as anti-inflammatory and anti-allergic/hypereosinophilic agents. We found that treatment with dexamethasone induced eosinophil apoptosis. In contrast, dexamethasone was a potent inhibitor of neutrophil apoptosis. The effect of dexamethasone on both cell types was mediated through the glucocorticoid receptor, i.e., it was abolished by the glucocorticoid receptor antagonist RU38486. This is the first description of an agent that promotes eosinophil apoptosis while inhibiting neutrophil apoptosis, and thus presents a novel approach to the study of control of apoptosis in these closely related cell types as well as increases our understanding of the clinical action of glucocorticoids in inflammation.