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Am. J. Respir. Cell Mol. Biol., Volume 23, Number 1, July, 2000 79-85

Synergistic Inhibition by beta 2-Agonists and Corticosteroids on Tumor Necrosis Factor-alpha -Induced Interleukin-8 Release from Cultured Human Airway Smooth-Muscle Cells

Linhua Pang and Alan J. Knox

Division of Respiratory Medicine, City Hospital, University of Nottingham, Nottingham, United Kingdom

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 µM) and fluticasone (Flut) (0.01 to 1 µM) but unaffected by Salbu, Salme, FSK, or 8-Br-cAMP. However, a combination of Dex (1 µM) or Flut (0.1 µM) with Salbu (10 µM), Salme (1 µM), FSK (10 µM), or 8-Br-cAMP (10 and 100 µM) 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.




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