Effects of dexamethasone on purinergic signaling in murine mast cells: Selective suppression of P2X7 receptor expression

Abstract

Mast cells express many different purinergic receptors, including ionotropic P2X4 and P2X7, which recognize the accumulation of extracellular ATP released from activated and/or damaged cells. This results in the stimulation of mast cell functions. In this study, we investigated the effects of dexamethasone (Dex), an anti-inflammatory glucocorticoid widely used for the treatment of allergic disease, on purinergic receptor expression in mouse bone marrow-derived mast cells (BMMCs). Treatment of BMMCs with Dex decreased P2X7 receptor mRNA levels in a time- and concentration-dependent manner without affecting the expression of other purinergic receptor subtypes. Accordingly, fluorescence-activated cell sorting analysis revealed that Dex treatment also decreased P2X7 receptor protein levels. This effect was mimicked by prednisolone, another anti-inflammatory glucocorticoid, and was inhibited by the glucocorticoid receptor antagonist mifepristone. Functionally, treatment of BMMCs with Dex impaired the P2X7-mediated rise in intracellular Ca2+ concentration, degranulation, and ethidium uptake, a response relevant to receptor-pore formation. Finally, oral administration of Dex to C57BL/6 mice in vivo resulted in a significant decrease in P2X7 receptor expression in peritoneal mast cells. These results suggest that reduction of P2X7 receptor expression in mast cells might be one of the anti-allergic mechanisms of Dex.