Divergent effect of mometasone on human eosinophil and neutrophil apoptosis.
Mometasone is a potent synthetic glucocorticoid, which is under development as an inhaled preparation for the treatment of asthma. Previous studies have suggested that glucocorticoids have direct effects on human eosinophil and neutrophil apoptosis. The present study was designed to characterize the effects of mometasone on constitutive apoptosis and cytokine-afforded survival in isolated human eosinophils and neutrophils. The isolated eosinophils or neutrophils were cultured in vitro, and apoptosis was assessed by flow cytometric analysis of relative DNA content, by annexin-V binding and morphological analysis. Mometasone enhanced constitutive human eosinophil apoptosis in a concentration-dependent manner. The maximal enhancement of eosinophil apoptosis was 2.1-fold with an EC(50) value of 5.63 +/- 2.33 nM. This enhancing effect was reversed by the glucocorticoid receptor antagonist, mifepristone. In the presence of added cytokines, mometasone reversed tumor necrosis factor -alpha-induced eosinophil survival but not that afforded by interleukin -5. In contrast, mometasone inhibited human neutrophil apoptosis in a concentration-dependent manner. The maximal inhibition of neutrophil apoptosis was 50% with an EC(50) value of 0.17 +/- 0.03 nM. The inhibitory effect was partly reversed by mifepristone. In the presence of added cytokines, mometasone further enhanced neutrophil survival induced by the granulocyte-macrophage colony-stimulating factor and leukotriene B(4). The present data suggests that mometasone has opposite effects on apoptosis of human eosinophils and neutrophils at clinically relevant drug concentrations via an effect on glucocorticoid receptor.
Zhang
Xianzhi
X
The Immunopharmacological Research Group, Medical School, University of Tampere, FIN-33014 Tampere, Finland.
Moilanen
Eeva
E
Adcock
Ian M
IM
Lindsay
Mark A
MA
Kankaanranta
Hannu
H
D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D004247:DNA / Q000032:analysis; D053938:DNA Fragmentation; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D004804:Eosinophils / Q000187:drug effects* / Q000473:pathology; D005434:Flow Cytometry; D005938:Glucocorticoids / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D015848:Interleukin-5 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D007975:Leukotriene B4 / Q000494:pharmacology; D015735:Mifepristone / Q000494:pharmacology; D000068656:Mometasone Furoate; D009504:Neutrophils / Q000187:drug effects* / Q000473:pathology; D011244:Pregnadienediols / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D005938:Glucocorticoids; D006727:Hormone Antagonists; D015848:Interleukin-5; D015850:Interleukin-6; D011244:Pregnadienediols; D014409:Tumor Necrosis Factor-alpha; D000068656:Mometasone Furoate; D007975:Leukotriene B4; D015735:Mifepristone; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D004247:DNA