Transforming Growth Factor-β1 Decreases β<sub>2</sub>-Agonist–induced Relaxation in Human Airway Smooth Muscle

Ojiaku, Christie A.; Chung, Elena; Parikh, Vishal; Williams, Jazmean K.; Schwab, A.; Fuentes, Ana Lucía; Corpuz, Maia L.; Lui, Victoria; Paek, Sam; Bexiga, Natalia Marchesan; Narayan, Shreya; Núñez, Francisco; Ahn, Kwangmi; Ostrom, Rennolds S.; An, Steven S.; Panettieri, Reynold A.

doi:10.1165/rcmb.2018-0301oc

Cited by 23 publications

(21 citation statements)

References 67 publications

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“…63 Similarly, activation of TGF-β by αvβ8 integrin on DCs was required for production of IL-17A by CD4 + αβ T cells following peripheral allergen sensitization and airway challenge in mice, with IL-17A shown to promote contraction of murine and human airway smooth muscle cells (ASMCs) in vitro. 64 In addition, overnight TGF-β1 exposure has been shown to increase contractility of human ASMCs and to desensitize these cells to relaxation by β 2 adrenergic receptor agonists, 65,66 suggesting that TGF-β itself may directly promote AHR in some contexts. TGF-β also has potential to drive pathogenic airway structural changes, since hyperactivation of TGF-β signaling in the conducting airway epithelium by overexpression of Smad2 enhanced airway remodeling and AHR in mice exposed to inhaled ovalbumin without prior sensitization, 67 or mice repeatedly administered inhaled HDM.…”

Section: Protective and Pathogenic Effects Of Tgf-β In Allergic Airwamentioning

confidence: 99%

Regulatory cytokine function in the respiratory tract

Branchett

Lloyd

2019

Mucosal Immunology

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The respiratory tract is an important site of immune regulation; required to allow protective immunity against pathogens, while minimizing tissue damage and avoiding aberrant inflammatory responses to inhaled allergens. Several cell types work in concert to control pulmonary immune responses and maintain tolerance in the respiratory tract, including regulatory and effector T cells, airway and interstitial macrophages, dendritic cells and the airway epithelium. The cytokines transforming growth factor β, interleukin (IL-) 10, IL-27, and IL-35 are key coordinators of immune regulation in tissues such as the lung. Here, we discuss the role of these cytokines during respiratory infection and allergic airway disease, highlighting the critical importance of cellular source and immunological context for the effects of these cytokines in vivo.

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Section: Protective and Pathogenic Effects Of Tgf-β In Allergic Airwamentioning

confidence: 99%

Regulatory cytokine function in the respiratory tract

Branchett

Lloyd

2019

Mucosal Immunology

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“…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 also demonstrated that TGF-β1 blunts intracellular cAMP by upregulating pde4d expression that decreases β 2 -agonist-induced cAMP levels [11].…”

Section: Introductionmentioning

confidence: 67%

“…Others have demonstrated that dexamethasone, a glucocorticoid, can directly inhibit Smad3 activity [16,17]. Our previous study showed that TGF-β1 blunted the effects of β 2 agonist-induced reversal of carbachol-mediated phosphorylation of myosin light chain, a process which was Smad3-dependent [11]. Given this information, we posited that GC treatment would reverse TGF-β1-induced hyporesponsiveness to β 2 -agonist.…”

Section: Introductionmentioning

confidence: 81%

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

et al. 2020

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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.

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“…In the final example, a downstream cellular response was found to conform to the profile, relaxation of human airway smooth muscle cells via the β 2 adrenoceptor ( Supplementary Fig. S2i) 52 . .…”

Section: Association Exponential Time Course Profilementioning

confidence: 86%

Analyzing kinetic signaling data for G-protein-coupled receptors

Hoare¹,

Tewson

Quinn

et al. 2020

Preprint

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In classical pharmacology, bioassay data are fit to general equations (e.g. the dose response equation) to determine empirical drug parameters (e.g. EC 50 and E max ), which are then used to calculate chemical parameters such as affinity and efficacy. Here we used a similar approach for kinetic, time course signaling data, to allow empirical and chemical definition of signaling by Gprotein-coupled receptors in kinetic terms. Experimental data are analyzed using general time course equations (model-free approach) and mechanistic model equations (mechanistic approach) in the commonly-used curve-fitting program, GraphPad Prism. A literature survey indicated signaling time course data usually conform to one of four curve shapes: the straight line, association exponential curve, rise-and-fall to zero curve, and rise-and-fall to steady-state curve. In the model-free approach, the initial rate of signaling is quantified and this is done by curve-fitting to the whole time course, avoiding the need to select the linear part of the curve. It is shown that the four shapes are consistent with a mechanistic model of signaling, based on enzyme kinetics, with the shape defined by the regulation of signaling mechanisms (e.g. receptor desensitization, signal degradation). Signaling efficacy is the initial rate of signaling by agonistoccupied receptor (k τ ), simply the rate of signal generation before it becomes affected by regulation mechanisms, measurable using the model-free analysis. Regulation of signaling parameters such as the receptor desensitization rate can be estimated if the mechanism is known. This study extends the empirical and mechanistic approach used in classical pharmacology to kinetic signaling data, facilitating optimization of new therapeutics in kinetic terms.

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Transforming Growth Factor-β1 Decreases β₂-Agonist–induced Relaxation in Human Airway Smooth Muscle

Cited by 23 publications

References 67 publications

Regulatory cytokine function in the respiratory tract

Regulatory cytokine function in the respiratory tract

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

Analyzing kinetic signaling data for G-protein-coupled receptors

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Transforming Growth Factor-β1 Decreases β2-Agonist–induced Relaxation in Human Airway Smooth Muscle

Cited by 23 publications

References 67 publications

Regulatory cytokine function in the respiratory tract

Regulatory cytokine function in the respiratory tract

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

Analyzing kinetic signaling data for G-protein-coupled receptors

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Transforming Growth Factor-β1 Decreases β₂-Agonist–induced Relaxation in Human Airway Smooth Muscle