Abstract
Glucocorticoids (GCs) and β2-adrenergic receptor (β2AR) 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- β1 (TGF-β1) increases phosphodiesterase 4D (PDE4D) expression that attenuates agonist-induced levels of intracellular cAMP. Decreased cAMP levels then diminishes β2 agonist-induced airway relaxation. In the current study, we investigated whether glucocorticoids reverse TGF-β1-effects on β2-agonist-induced bronchodilation and modulate pde4d gene expression in HASM. Dexamethasone (DEX) reversed TGF-β1 effects on cAMP levels induced by isoproterenol (ISO). TGF-β1 also attenuated G protein-dependent responses to cholera toxin (CTX), a Gαs stimulator downstream from the β2AR receptor. Previously, we demonstrated that TGF-β1 treatment increased β2AR phosphorylation to induce hyporesponsiveness to a β2 agonist. Our current data shows that expression of grk2/3, kinases associated with attenuation of β2AR function, are not altered with TGF-β1 stimulation. Interestingly, DEX also attenuated TGF-β1-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-β1 levels.
Highlights
Asthma, a chronic inflammatory disease of the lungs manifests by several hallmarks: airway hyperresponsiveness, remodeling, and inflammation [1]
To further understand mechanisms underlying TGF-β1mediated hyporesponsiveness to a β2-agonist, intracellular Adenosine 3′ (cAMP) levels were measured in transforming growth factor- β1 (TGF-β1)-treated human airway smooth muscle (HASM) cells following stimulation with cholera toxin (CTX), a Gαs activator
Intracellular cAMP activity increased in a time-dependent manner following exposure to CTX, with the maximum level elicited at 45 min (Fig. 1a)
Summary
A chronic inflammatory disease of the lungs manifests by several hallmarks: airway hyperresponsiveness, remodeling, and inflammation [1]. Airway smooth muscle (ASM) cells play an integral role in regulating bronchomotor tone in the asthma diatheses and are a. Chung et al Respiratory Research (2020) 21:256 direct target of β2-agonists, a common therapy that promotes bronchodilation [2]. Patients who fall into the “severe” category of asthma are frequently hyporesponsive to bronchodilators [4]. TGF-β1, a profibrotic cytokine whose levels are elevated in patients with asthma, augments human airway smooth muscle (HASM) cell stiffness and significantly increases myosin light chain (MLC) phosphorylation via Smad3 [10] that enhance contractile agonist-induced cell shortening and hyperresponsiveness. In addition to amplifying bronchoconstriction, we demonstrated that TGF-β1 blunts intracellular cAMP by upregulating pde4d expression that decreases β2-agonist-induced cAMP levels [11]
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