Selected Contribution: Synergism between TNF-a and IL-1ß in airway smooth
muscle cells: implications for ß-adrenergic responsiveness.
Moore, Paul E., Thomas Lahiri, Johanne D. Laporte, Trudi Church, Reynold A. Panettieri
Jr., and Stephanie A. Shore.
1Physiology Program, Harvard School of Public Health, Boston, Massachusetts
02115; and 2Pulmonary and Critical Care Division, Department of Medicine, University
of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104
APStracts 8:0326A, 2001.
In human cultured airway smooth muscle cells, interleukin (IL)-1ß increases
cyclooxygenase (COX)-2 expression and PGE2 release, ultimately resulting in decreased
ß-adrenergic responsiveness. In this study, we aimed to determine whether tumor
necrosis factor-«alpha» (TNF-a) synergizes with IL-1ß in the induction of these events.
TNF-a alone, at concentrations up to 10 ng/ml, had no effect on COX-2 protein
expression; at concentrations as low as 0.1 ng/ml, it significantly enhanced the ability of
IL-1ß (0.2 ng/ml) to induce COX-2 and to increase PGE2 release. IL-1ß and TNF-a in
combination also significantly enhanced COX-2 promoter activity, indicating that
synergism between the cytokines is mediated at the level of gene transcription. Although
IL-1ß and TNF-a each increased nuclear factor-?B activation and induced extracellular
regulated kinase and p38 phosphorylation, combined administration of the cytokines did
not enhance either nuclear factor-?B or mitogen-activated protein kinase activation.
Combined administration of IL-1ß (0.2 ng/ml) and TNF-a (0.1 or 1.0 ng/ml) reduced the
ability of isoproterenol to decrease human airway smooth muscle cell stiffness, as
measured by magnetic twisting cytometry, even though individually these cytokines, at
these concentrations, had no effect on isoproterenol responses. Treatment with the
selective COX-2 inhibitor NS-398 abolished the synergistic effects of TNF-a and IL-1ß
on ß-adrenergic responsiveness. Our results indicate that low concentrations of IL-1ß and
TNF-a synergize to promote ß-adrenergic hyporesponsiveness and that effects on COX-2
expression and PGE2 are responsible for these events. The data suggest that the
simultaneous release in the airway, of even very small amounts of cytokines, can have
important functional consequences.
Received 3 April 2001; accepted in final form 14 June 2001
APS Manuscript Number A318-1.
Article publication pending J Appl Physiol
ISSN 1080-4757 Copyright 2001 The American Physiological Society.
Published in APStracts on 29 June 2001