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Dexamethasone rescues TGF-?1-mediated ?2-adrenergic receptor dysfunction and attenuates phosphodiesterase 4D expression in human airway smooth muscle cells.

ABSTRACT: Glucocorticoids (GCs) and ?2-adrenergic receptor (?2AR) 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- ?1 (TGF-?1) increases phosphodiesterase 4D (PDE4D) expression that attenuates agonist-induced levels of intracellular cAMP. Decreased cAMP levels then diminishes ?2 agonist-induced airway relaxation. In the current study, we investigated whether glucocorticoids reverse TGF-?1-effects on ?2-agonist-induced bronchodilation and modulate pde4d gene expression in HASM. Dexamethasone (DEX) reversed TGF-?1 effects on cAMP levels induced by isoproterenol (ISO). TGF-?1 also attenuated G protein-dependent responses to cholera toxin (CTX), a G?s stimulator downstream from the ?2AR receptor. Previously, we demonstrated that TGF-?1 treatment increased ?2AR phosphorylation to induce hyporesponsiveness to a ?2 agonist. Our current data shows that expression of grk2/3, kinases associated with attenuation of ?2AR function, are not altered with TGF-?1 stimulation. Interestingly, DEX also attenuated TGF-?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-?1 levels.

SUBMITTER: Chung E

PROVIDER: S-EPMC7545943 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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

Chung Elena E Ojiaku Christie A CA Cao Gaoyuan G Parikh Vishal V Deeney Brian B Xu Shengjie S Wang Serena S Panettieri Reynold A RA Koziol-White Cynthia C

Respiratory research 20201008 1

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 cA ...[more]

PMID: 33032603

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Project description:Transforming Growth Factor Beta1 (TGF-β1) signaling is upregulated in Chronic Obstructive Pulmonary disease (COPD), smokers, and people living with HIV. Cigarette smoking and HIV are also independent risk factors for COPD. Chronic inflammation is a hallmark of COPD. However, the underlying mechanisms remain unknown. Previous research has suggested that TGF-β1 alters the airway epithelial microRNAome and transcriptome, potentially contributing to lung inflammation. The Lactoperoxidase (LPO) system is an integral component of innate immunity within the airway. LPO plays a crucial role in host defense by catalyzing the oxidation of thiocyanate to hypothiocyanite in the presence of hydrogen peroxide (H2O2), generating a potent antibacterial and antiviral agent. Additionally, the LPO system potentially aids in maintaining cellular redox balance by reducing the levels of H2O2, thus mitigating oxidative stress within the airway epithelium. LPO dysfunction can impair immune responses and exacerbate inflammatory processes in respiratory diseases.In this study, primary bronchial epithelial cells and bronchial cell lines were treated with TGF-β1 and exposed to cigarette smoke to characterize the effect of these factors on LPO and their downstream effects. RT-qPCR and Western Blot were applied to quantify mRNA and proteins' expression. The levels of H2O2 were detected using the Amplex Red Assay. Magnetofection and transfection were applied to probe the effect of miR-449b-5p. Staining procedures using the MitoTracker Green and C12FDG dyes were used to establish mitochondria mass and senescence. The levels of pro-inflammatory cytokines were measured via Luminex assays.We found that TGF-β1 and cigarette smoke suppressed airway LPO expression, increasing H2O2 levels. This increase in H2O2 had downstream effects on mitochondrial homeostasis, epithelial cellular senescence, and the pro-inflammatory cytokine response. We demonstrate for the first time that airway LPO is regulated by TGF-β1-induced miRNA-mediated post-transcriptional silencing through miR-449b-5p in the lungs. Further, we identify and validate miR-449-5p as the candidate miRNA upregulated by TGF-β1, which is involved in LPO suppression. This paper demonstrates a new mechanism by which TGF-β1 can lead to altered redox status in the airway.

Dataset Information

Dexamethasone rescues TGF-?1-mediated ?2-adrenergic receptor dysfunction and attenuates phosphodiesterase 4D expression in human airway smooth muscle cells.

Publications

Dexamethasone rescues TGF-β1-mediated β<sub>2</sub>-adrenergic receptor dysfunction and attenuates phosphodiesterase 4D expression in human airway smooth muscle cells.

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