Background: Activation of the β₂-adrenergic receptor (β₂AR) system expressed by human airway epithelial cells elicits a variety of cyclic adenosine monophosphate (cAMP)-dependent processes that help determine airway caliber and the intensity of airway inflammation in asthma. Glucocorticoids, mainstays in the treatment of asthma, profoundly affect the expression and function of the β₂-adrenergic receptor-adenylyl cyclase (β₂AR-AC) system in a variety of cell types. However, the effects of glucocorticoids on the β₂AR-AC system expressed by human airway epithelial cells are unstudied. Objective: We examined the effects of dexamethasone (DEX) on β₂AR gene expression and the function of the β₂AR-AC system in cultured human airway epithelial cells. Methods: Studies were performed in normal airway epithelial cells and BEAS-2B cells. β₂AR gene expression was assessed from measurements of β-adrenergic receptor density, β₂AR mRNA, and the activity of a full-length β₂AR promoter-luciferase reporter construct. The function of the β₂AR-AC system was assessed from cAMP production in response to the β₂-agonist isoproterenol and the expression of the stimulatory G protein G⍺s. Results: DEX had no effect on β-adrenergic receptor density or on the β₁/β₂ ratio over a wide range of concentrations and exposure times. However, DEX significantly but transiently enhanced β₂AR mRNA levels (~1.5-fold) and β₂AR promoter activity (~1.5-fold), indicating increased β₂AR gene transcription. DEX also dose-dependently enhanced cAMP responses to isoproterenol but not to forskolin, a direct activator of adenylyl cyclase. DEX-induced changes in cAMP production were associated with small (~15%) increases in G⍺s expression. Conclusions: These data indicate that glucocorticoids only transiently enhance β₂AR gene transcription and fail to increase steady-state levels of β₂AR protein in human airway epithelial cells. Nonetheless, glucocorticoid-induced effects on the β₂AR-AC system of human airway epithelial cells contribute to the beneficial effects of corticosteroids in asthma by enhancing the functional response to β₂-agonists. (J Allergy Clin Immunol 2002;109:491-7.)