Synergistic inhibition by beta(2)-agonists and corticosteroids on tumor necrosis factor-alpha-induced interleukin-8 release from cultured human airway smooth-muscle cells

Am J Respir Cell Mol Biol. 2000 Jul;23(1):79-85. doi: 10.1165/ajrcmb.23.1.3985.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 8-Bromo Cyclic Adenosine Monophosphate / pharmacology
  • Adrenal Cortex Hormones / pharmacology*
  • Adrenal Cortex Hormones / therapeutic use
  • Adrenergic beta-2 Receptor Antagonists
  • Adrenergic beta-Agonists / pharmacology*
  • Adrenergic beta-Agonists / therapeutic use
  • Adrenergic beta-Antagonists / pharmacology
  • Albuterol / analogs & derivatives
  • Albuterol / pharmacology
  • Albuterol / therapeutic use
  • Androstadienes / pharmacology
  • Androstadienes / therapeutic use
  • Asthma / drug therapy
  • Cell Survival / drug effects
  • Cells, Cultured
  • Colforsin / pharmacology
  • Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Dexamethasone / pharmacology
  • Dexamethasone / therapeutic use
  • Drug Synergism
  • Fluticasone
  • Humans
  • Interleukin-8 / metabolism*
  • Muscle, Smooth / cytology
  • Muscle, Smooth / drug effects*
  • Muscle, Smooth / metabolism
  • Phosphodiesterase Inhibitors / pharmacology
  • Propanolamines / pharmacology
  • Receptors, Adrenergic, beta-2 / metabolism
  • Respiratory System / cytology
  • Respiratory System / drug effects*
  • Rolipram / pharmacology
  • Salmeterol Xinafoate
  • Trachea / cytology
  • Trachea / drug effects
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Adrenal Cortex Hormones
  • Adrenergic beta-2 Receptor Antagonists
  • Adrenergic beta-Agonists
  • Adrenergic beta-Antagonists
  • Androstadienes
  • Interleukin-8
  • Phosphodiesterase Inhibitors
  • Propanolamines
  • Receptors, Adrenergic, beta-2
  • Tumor Necrosis Factor-alpha
  • Colforsin
  • 8-Bromo Cyclic Adenosine Monophosphate
  • ICI 118551
  • Salmeterol Xinafoate
  • Dexamethasone
  • Fluticasone
  • Cyclic AMP-Dependent Protein Kinases
  • Rolipram
  • Albuterol