Dexamethasone rescues TGF-β1-mediated β2-adrenergic receptor dysfunction and attenuates phosphodiesterase 4D expression in human airway smooth muscle cells

Glucocorticoids (GCs) and beta (2)-adrenergic receptor (beta (2)AR) agonists improve asthma outcomes in most patients. GCs also modulate gene expression in human airway smooth muscle (HASM), thereby attenuating airway inflammation and airway hyperresponsiveness that define asthma. Our previous studies showed that the pro-fibrotic cytokine, transforming growth factor- beta 1 (TGF-beta 1) increases phosphodiesterase 4D (PDE4D) expression that attenuates agonist-induced levels of intracellular cAMP. Decreased cAMP levels then diminishes beta (2) agonist-induced airway relaxation. In the current study, we investigated whether glucocorticoids reverse TGF-beta 1-effects on beta (2)-agonist-induced bronchodilation and modulate pde4d gene expression in HASM. Dexamethasone (DEX) reversed TGF-beta 1 effects on cAMP levels induced by isoproterenol (ISO). TGF-beta 1 also attenuated G protein-dependent responses to cholera toxin (CTX), a G(alpha s) stimulator downstream from the beta (2)AR receptor. Previously, we demonstrated that TGF-beta 1 treatment increased beta (2)AR phosphorylation to induce hyporesponsiveness to a beta (2) agonist. Our current data shows that expression of grk2/3, kinases associated with attenuation of beta (2)AR function, are not altered with TGF-beta 1 stimulation. Interestingly, DEX also attenuated TGF-beta 1-induced pde4d gene expression. These data suggest that steroids may be an effective therapy for treatment of asthma patients whose disease is primarily driven by elevated TGF-beta 1 levels.