Abstract
We have previously reported that human airway smooth-muscle (ASM) cells produce abundant interleukin (IL)-8, a major neutrophil chemoattractant involved in asthma exacerbations. Here, we tested the effects of the beta(2)-agonists salbutamol (Salbu) and salmeterol (Salme) on IL-8 release and tumor necrosis factor (TNF)-alpha-induced IL-8 release from ASM cells. We found that TNF-alpha strongly enhanced IL-8 release in a time- and concentration-dependent manner, whereas Salbu, Salme, the direct adenylyl cyclase activator forskolin (FSK), and the cyclic monophosphate (cAMP) analogue 8-bromoadenosine 3',5'-cAMP (8-Br-cAMP) alone weakly stimulated IL-8 release. TNF-alpha (10 ng/ml)-induced IL-8 release was markedly inhibited by the steroids dexamethasone (Dex) (0.1 to 10 microM) and fluticasone (Flut) (0.01 to 1 microM) but unaffected by Salbu, Salme, FSK, or 8-Br-cAMP. However, a combination of Dex (1 microM) or Flut (0.1 microM) with Salbu (10 microM), Salme (1 microM), FSK (10 microM), or 8-Br-cAMP (10 and 100 microM) significantly enhanced the inhibition by Dex or Flut alone. Experiments with KT5720, a selective inhibitor of cAMP-dependent protein kinase A; rolipram, a selective inhibitor of type IV phosphodiesterase; and ICI-118,551, a beta(2)-receptor antagonist, suggested that the synergistic inhibition was mediated by beta(2)-receptor in a cAMP-dependent manner. This novel synergistic interaction of beta(2)-agonists and steroids may partly explain the benefits that result when these agents are combined to treat asthma.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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8-Bromo Cyclic Adenosine Monophosphate / pharmacology
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Adrenal Cortex Hormones / pharmacology*
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Adrenal Cortex Hormones / therapeutic use
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Adrenergic beta-2 Receptor Antagonists
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Adrenergic beta-Agonists / pharmacology*
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Adrenergic beta-Agonists / therapeutic use
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Adrenergic beta-Antagonists / pharmacology
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Albuterol / analogs & derivatives
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Albuterol / pharmacology
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Albuterol / therapeutic use
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Androstadienes / pharmacology
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Androstadienes / therapeutic use
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Asthma / drug therapy
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Cell Survival / drug effects
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Cells, Cultured
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Colforsin / pharmacology
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Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
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Cyclic AMP-Dependent Protein Kinases / metabolism
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Dexamethasone / pharmacology
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Dexamethasone / therapeutic use
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Drug Synergism
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Fluticasone
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Humans
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Interleukin-8 / metabolism*
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Muscle, Smooth / cytology
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Muscle, Smooth / drug effects*
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Muscle, Smooth / metabolism
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Phosphodiesterase Inhibitors / pharmacology
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Propanolamines / pharmacology
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Receptors, Adrenergic, beta-2 / metabolism
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Respiratory System / cytology
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Respiratory System / drug effects*
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Rolipram / pharmacology
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Salmeterol Xinafoate
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Trachea / cytology
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Trachea / drug effects
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Tumor Necrosis Factor-alpha / antagonists & inhibitors*
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Tumor Necrosis Factor-alpha / pharmacology
Substances
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Adrenal Cortex Hormones
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Adrenergic beta-2 Receptor Antagonists
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Adrenergic beta-Agonists
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Adrenergic beta-Antagonists
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Androstadienes
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Interleukin-8
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Phosphodiesterase Inhibitors
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Propanolamines
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Receptors, Adrenergic, beta-2
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Tumor Necrosis Factor-alpha
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Colforsin
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8-Bromo Cyclic Adenosine Monophosphate
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ICI 118551
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Salmeterol Xinafoate
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Dexamethasone
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Fluticasone
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Cyclic AMP-Dependent Protein Kinases
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Rolipram
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Albuterol