Glucocorticoids inhibit degranulation of mast cells in allergic asthma via nongenomic mechanism

Background: Glucocorticoids (GCs) are the most potent anti-inflammatory agents available for allergic diseases including asthma, which are routinely believed to need several hours to take effect through regulating gene expression. Our previous report had shown that GCs could inhibit allergic asthma within 10 min, which the classical mechanism could not explain. Objective: To confirm the existence and verify the sites of GCs' rapid action, we investigated nongenomic effects of GCs on degranulation of mast cells in allergic asthma. Methods: The GCs' rapid action on airway mast cells deregulations was evaluated in the allergic asthma model of guinea pigs by the computer-assisted morphometry. Using whole-cell patch clamp and fluorometric assay, we examined GCs' nongenomic effect on IgE-mediated exocytosis and histamine release of rat basophilic leukaemia-2H3 mast cells. Employing the flash photolysis technique, we studied the role of Ca2+ signal in the GCs' nongenomic effect. Results: Inhaled GCs significantly inhibited airway mast cells degranulation in the allergic asthma model of guinea pigs within 10 min. In vitro, GCs could rapidly inhibit IgE-mediated exocytosis and histamine release of mast cells, and neither GC nuclear receptor antagonist nor protein synthesis inhibitor could block the rapid action. We further demonstrated that GCs' nongenomic effect was not through direct action on secretory machinery, but was mediated by a reduction in the [Ca2+](i) elevation. Conclusions: The study suggested for the first time that nongenomic pathway was involved in GCs' rapid inhibition on allergic asthma, and raised the possibility of new therapeutic strategies for allergic diseases including asthma.