TNF-alpha inhibits isoproterenol-stimulated adenylyl cyclase activity in cultured airway smooth muscle cells

• Published in: The American journal of physiology Vol. 272; no. 4 Pt 1; p. L644
• Main Authors: Emala, C W, Kuhl, J, Hungerford, C L, Hirshman, C A
• Format: Journal Article
• Language: English
• Published: United States 01.04.1997
• Subjects: Adenosine Diphosphate Ribose - metabolism; Adenylate Cyclase Toxin; Adenylyl Cyclase Inhibitors; Adenylyl Cyclases - metabolism; Adrenergic beta-Agonists - pharmacology; Animals; Cells, Cultured; Dogs; GTP-Binding Proteins - metabolism; Isoproterenol - pharmacology; Muscle, Smooth - cytology; Muscle, Smooth - drug effects; Muscle, Smooth - enzymology; Trachea - cytology; Trachea - drug effects; Trachea - enzymology; Tumor Necrosis Factor-alpha - pharmacology; Virulence Factors, Bordetella - pharmacology
• ISSN: 0002-9513
• DOI: 10.1152/ajplung.1997.272.4.L644

Inflammation, increased cytokine production, and decreased responsiveness of airway smooth muscle (ASM) to beta-adrenergic agonists are characteristics of asthma. We questioned whether the cytokine tumor necrosis factor-alpha (TNF-alpha) directly impaired beta-adrenergic signal transduction in cultured canine ASM cells. Confluent ASM cells exposed to TNF-alpha (0.1-10 ng/ml) for 72 h showed lower maximal levels of adenylyl cyclase activity in response to isoproterenol (10 ng/ml; 14 +/- 4.3 vs. 7.5 +/- 1.3 pmol adenosine 3',5'-cyclic monophosphate x well(-1) x 20 min(-1), control vs. treated, respectively), despite no changes in beta-adrenergic receptor numbers (maximum number of binding sites = 4.8 +/- 0.72 vs. 4.5 +/- 0.81 fmol/mg protein, control vs. treated, respectively). Adenylyl cyclase activities in response to prostaglandin E1, NaF, or forskolin were not different in treated and untreated cells. These results demonstrate that a cytokine known to be increased during exacerbation of asthmatic symptoms directly impairs beta-adrenergic function in ASM cells and suggests a mechanism by which inflammation impairs beta-adrenergic receptor signal transduction in asthma.