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

• Published in: Biochemical and biophysical research communications 2017-12, Vol.493 (4), p.1587-1593
• Main Authors: Yoshida, Kazuki, Ito, Masaaki, Hoshino, Yui, Matsuoka, Isao
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents - pharmacology; Cell Degranulation - drug effects; Cells, Cultured; Dexamethasone; Dexamethasone - pharmacology; Down-Regulation - drug effects; Gene expression; Glucocorticoid receptor; Mast cells; Mast Cells - drug effects; Mast Cells - physiology; Mice; Mice, Inbred C57BL; P2X7 receptor; Purinergic P2X Receptor Antagonists - pharmacology; Receptors, Purinergic P2X1 - genetics; Receptors, Purinergic P2X1 - metabolism; Receptors, Purinergic P2X4 - genetics; Receptors, Purinergic P2X4 - metabolism; Receptors, Purinergic P2X7 - genetics; Receptors, Purinergic P2X7 - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction - drug effects
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2017.10.020

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. •Dexamethasone (Dex) downregulates P2X7 in bone marrow-derived mast cells (BMMCs).•Prednisolone mimics, while mifepristone inhibits, these effects.•Dex impairs Ca2+ increase, degranulation, and ethidium uptake in BMMCs.•Oral administration of Dex downregulates P2X7 in murine peritoneal mast cells.