Synergistic inhibition by beta(2)-agonists and corticosteroids on tumor necrosis factor-alpha-induced interleukin-8 release from cultured human airway smooth-muscle cells.
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.
Pang
L
L
Division of Respiratory Medicine, City Hospital, University of Nottingham, Nottingham, United Kingdom.
Knox
A J
AJ
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000305:Adrenal Cortex Hormones / Q000494:pharmacology* / Q000627:therapeutic use; D058672:Adrenergic beta-2 Receptor Antagonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000420:Albuterol / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000730:Androstadienes / Q000494:pharmacology / Q000627:therapeutic use; D001249:Asthma / Q000188:drug therapy; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology / Q000627:therapeutic use; D004357:Drug Synergism; D000068298:Fluticasone; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism*; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism; D012137:Respiratory System / Q000166:cytology / Q000187:drug effects*; D020889:Rolipram / Q000494:pharmacology; D000068299:Salmeterol Xinafoate; D014132:Trachea / Q000166:cytology / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000494:pharmacology
D000305:Adrenal Cortex Hormones; D058672:Adrenergic beta-2 Receptor Antagonists; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D000730:Androstadienes; D016209:Interleukin-8; D010726:Phosphodiesterase Inhibitors; D011412:Propanolamines; D018343:Receptors, Adrenergic, beta-2; D014409:Tumor Necrosis Factor-alpha; D005576:Colforsin; D015124:8-Bromo Cyclic Adenosine Monophosphate; C026777:ICI 118551; D000068299:Salmeterol Xinafoate; D003907:Dexamethasone; D000068298:Fluticasone; D017868:Cyclic AMP-Dependent Protein Kinases; D020889:Rolipram; D000420:Albuterol