Open AccessTransforming Growth Factor-β1 Decreases β2-Agonist–induced Relaxation in Human Airway Smooth Muscle
Author(s) -
Christie A. Ojiaku,
Elena Chung,
Vishal Parikh,
Jazmean K. Williams,
Anthony Schwab,
Ana Lucía Fuentes,
Maia L. Corpuz,
Victoria Lui,
Sam Paek,
Natália Marchesan Bexiga,
Shreya Narayan,
Francisco Núñez,
Kwangmi Ahn,
Rennolds S. Ostrom,
Steven S. An,
Reynold A. Panettieri
Publication year - 2019
Publication title -
american journal of respiratory cell and molecular biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.469
H-Index - 161
eISSN - 1535-4989
pISSN - 1044-1549
DOI - 10.1165/rcmb.2018-0301oc
Subject(s) - transforming growth factor , agonist , endocrinology , intracellular , phosphodiesterase , medicine , carbachol , cytokine , signal transduction , transforming growth factor beta , contractility , myosin light chain kinase , chemistry , myosin , immunology , microbiology and biotechnology , biology , receptor , biochemistry , enzyme
Helper T effector cytokines implicated in asthma modulate the contractility of human airway smooth muscle (HASM) cells. We have reported recently that a profibrotic cytokine, transforming growth factor (TGF)-β1, induces HASM cell shortening and airway hyperresponsiveness. Here, we assessed whether TGF-β1 affects the ability of HASM cells to relax in response to β 2 -agonists, a mainstay treatment for airway hyperresponsiveness in asthma. Overnight TGF-β1 treatment significantly impaired isoproterenol (ISO)-induced relaxation of carbachol-stimulated, isolated HASM cells. This single-cell mechanical hyporesponsiveness to ISO was corroborated by sustained increases in myosin light chain phosphorylation. In TGF-β1-treated HASM cells, ISO evoked markedly lower levels of intracellular cAMP. These attenuated cAMP levels were, in turn, restored with pharmacological and siRNA inhibition of phosphodiesterase 4 and Smad3, respectively. Most strikingly, TGF-β1 selectively induced phosphodiesterase 4D gene expression in HASM cells in a Smad2/3-dependent manner. Together, these data suggest that TGF-β1 decreases HASM cell β 2 -agonist relaxation responses by modulating intracellular cAMP levels via a Smad2/3-dependent mechanism. Our findings further define the mechanisms underlying β 2 -agonist hyporesponsiveness in asthma, and suggest TGF-β1 as a potential therapeutic target to decrease asthma exacerbations in severe and treatment-resistant asthma.