Comparative Efficacy of Glucocorticoid Receptor Agonists on Th2 Cell Function and Attenuation by Progesterone

Abstract

Background: Corticosteroids (CS) suppress cytokine production and induce apoptosis of inflammatory cells. Prednisone and dexamethasone are oral CS prescribed for treating asthma exacerbations. While prednisone is more commonly prescribed, dexamethasone is long acting and a more potent glucocorticoid receptor (GR) agonist. It can be administered as a one or two dose regime, unlike the five to seven days required for prednisone, a feature that increases compliance. We compared the relative ability of these two oral CS to suppress type 2 inflammation. Since progesterone has affinity for the GR and women are more likely to relapse following an asthma exacerbation, we assessed its influence on CS action. Results: Dexamethasone suppressed the level of IL-5 and IL-13 mRNA within Th2 cells with 10-fold less than prednisolone (the active form of prednisone). Dexamethasone induced a higher proportion of apoptotic and dying cells than prednisolone, at all concentrations examined. Addition of progesterone reduced their capacity to drive cell death, though dexamethasone maintained significantly more killing activity. Progesterone blunted dexamethasone-induction of FKBP5 mRNA, indicating the mechanism of action was by interference of the GC:GR complex. Conclusions: Dexamethasone is both more potent and effective than prednisolone in suppressing type 2 cytokine levels and mediating apoptosis. Progesterone attenuated these anti-inflammatory effects, indicating its potential influence on corticosteroid responses in vivo . Collectively, our data suggest that when oral corticosteroid is required, dexamethasone may be better able to control type 2 inflammation, eliminate Th2 cells and ultimately lead to improved long-term outcomes. Further research in asthmatics is needed