Tnf[alpha] inhibits isoproterenol-stimulated adenylyl cyclase
activity in cultured airway smooth muscle cells.
Emala, C. W., J. Kuhl, C. L. Hungerford, and C. A. Hirshman.
Departments of Anesthesiology, Medicine and Environmental Health
Sciences, The Johns Hopkins Medical Institutions
APStracts 3:0200L, 1996.
Inflammation, increased cytokine production and decreased
responsiveness of airway smooth muscle to [beta]-adrenergic agonists
are characteristics of asthma. We questioned whether the cytokine
tumor necrosis factor (TNF[alpha]) directly impaired [beta]
-adrenergic signal transduction in cultured canine airway smooth
muscle (ASM) cells. Confluent ASM cells exposed to TNF[alpha] (0.1 -
10 ng/ml) for 72 hours showed lower maximal levels of adenylyl
cyclase activity in response to isoproterenol (10 ng/ml: 14 +/- 4.3
vs. 7.5 +/- 1.3 pmol cAMP/well/20 min, control vs. treated,
respectively) despite no changes in [beta]-adrenergic receptor
numbers (Bmax 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 airway smooth muscle cells and
suggests a mechanism by which inflammation impairs [beta]-adrenergic
receptor signal transduction in asthma.
Received 19 January 1996; accepted in final form 5 November 1996.
APS Manuscript Number L25-6.
Article publication pending Am. J. Physiol. (Lung Cell. Mol.
Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 31 December 1996