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

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

Research output: Contribution to journalArticle

Abstract

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 β2-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 β2-agonist relaxation responses by modulating intracellular cAMP levels via a Smad2/3-dependent mechanism. Our findings further define the mechanisms underlying β2-agonist hyporesponsiveness in asthma, and suggest TGF-β1 as a potential therapeutic target to decrease asthma exacerbations in severe and treatment-resistant asthma.

Original languageEnglish (US)
Pages (from-to)209-218
Number of pages10
JournalAmerican journal of respiratory cell and molecular biology
Volume61
Issue number2
DOIs
StatePublished - Aug 1 2019

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Transforming Growth Factors
Smooth Muscle Myocytes
Smooth Muscle
Muscle
Asthma
Isoproterenol
Type 4 Cyclic Nucleotide Phosphodiesterase
Cytokines
Myosin Light Chains
Carbachol
Phosphorylation
Small Interfering RNA
Gene expression
Pharmacology
Gene Expression
Cells

Keywords

  • human airway smooth muscle
  • relaxation
  • severe asthma
  • TGF-β1
  • β-agonists

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

Cite this

Ojiaku, C. A., Chung, E., Parikh, V., Williams, J. K., Schwab, A., Fuentes, A. L., ... Panettieri, R. A. (2019). Transforming Growth Factor-β1 Decreases β2-Agonist-induced Relaxation in Human Airway Smooth Muscle. American journal of respiratory cell and molecular biology, 61(2), 209-218. https://doi.org/10.1165/rcmb.2018-0301OC

Transforming Growth Factor-β1 Decreases β2-Agonist-induced Relaxation in Human Airway Smooth Muscle. / Ojiaku, Christie A.; Chung, Elena; Parikh, Vishal; Williams, Jazmean K.; Schwab, Anthony; Fuentes, Ana Lucia; Corpuz, Maia L.; Lui, Victoria; Paek, Sam; Bexiga, Natalia M.; Narayan, Shreya; Nunez, Francisco J.; Ahn, Kwangmi; Ostrom, Rennolds S.; An, Steven; Panettieri, Reynold A.

In: American journal of respiratory cell and molecular biology, Vol. 61, No. 2, 01.08.2019, p. 209-218.

Research output: Contribution to journalArticle

Ojiaku, CA, Chung, E, Parikh, V, Williams, JK, Schwab, A, Fuentes, AL, Corpuz, ML, Lui, V, Paek, S, Bexiga, NM, Narayan, S, Nunez, FJ, Ahn, K, Ostrom, RS, An, S & Panettieri, RA 2019, 'Transforming Growth Factor-β1 Decreases β2-Agonist-induced Relaxation in Human Airway Smooth Muscle', American journal of respiratory cell and molecular biology, vol. 61, no. 2, pp. 209-218. https://doi.org/10.1165/rcmb.2018-0301OC
Ojiaku, Christie A. ; Chung, Elena ; Parikh, Vishal ; Williams, Jazmean K. ; Schwab, Anthony ; Fuentes, Ana Lucia ; Corpuz, Maia L. ; Lui, Victoria ; Paek, Sam ; Bexiga, Natalia M. ; Narayan, Shreya ; Nunez, Francisco J. ; Ahn, Kwangmi ; Ostrom, Rennolds S. ; An, Steven ; Panettieri, Reynold A. / Transforming Growth Factor-β1 Decreases β2-Agonist-induced Relaxation in Human Airway Smooth Muscle. In: American journal of respiratory cell and molecular biology. 2019 ; Vol. 61, No. 2. pp. 209-218.
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