Synergistic Inhibition by β2-Agonists and Corticosteroids on Tumor Necrosis Factor- α –Induced Interleukin-8 Release from Cultured Human Airway Smooth-Muscle Cells

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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 β2-agonists salbutamol (Salbu) and salmeterol (Salme) on IL-8 release and tumor necrosis factor (TNF)- α –induced IL-8 release from ASM cells. We found that TNF- α 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- α (10 ng/ml)–induced IL-8 release was markedly inhibited by the steroids dexamethasone (Dex) (0.1 to 10 μ M) and fluticasone (Flut) (0.01 to 1 μ M) but unaffected by Salbu, Salme, FSK, or 8-Br-cAMP. However, a combination of Dex (1 μ M) or Flut (0.1 μ M) with Salbu (10 μ M), Salme (1 μ M), FSK (10 μ M), or 8-Br-cAMP (10 and 100 μ M) 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 β2-receptor antagonist, suggested that the synergistic inhibition was mediated by β2-receptor in a cAMP-dependent manner. This novel synergistic interaction of β2-agonists and steroids may partly explain the benefits that result when these agents are combined to treat asthma.