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and IL-1
in airway smooth
muscle cells: implications for -adrenergic responsiveness
1 Physiology Program, Harvard School of Public Health, Boston, Massachusetts 02115; and 2 Pulmonary and Critical Care Division, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104
In human cultured airway smooth muscle cells, interleukin
(IL)-1
increases cyclooxygenase (COX)-2 expression and
PGE2 release, ultimately resulting in decreased
-adrenergic responsiveness. In this study, we aimed to determine
whether tumor necrosis factor-
(TNF-) synergizes with IL-1 in
the induction of these events. TNF- 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-1
(0.2 ng/ml) to induce COX-2 and to increase PGE2 release.
IL-1 and TNF- 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-1 and
TNF- 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-1 (0.2 ng/ml) and TNF- (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- and
IL-1 on -adrenergic responsiveness. Our results indicate that low
concentrations of IL-1 and TNF- synergize to promote
-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.
isoproterenol; cyclooxygenase-2; mitogen-activated protein
kinase; nuclear factor-B; magnetic twisting cytometry; interleukin-1; tumor necrosis factor-
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