β₂-adrenoceptor agonists enhance cytokine-induced release of thymic stromal lymphopoietin by lung tissue cells

Background: Whileβ₂-adrenoceptor agonists (β₂-agonists) are widely used as bronchodilators in the treatment of asthma, there has been increasing concern that regular use of β₂-agonists may adversely affect the control of asthma. However, the molecular mechanisms of such undesirable effects of β₂- agonists are not fully understood. In this study, we examined the effects of β₂-agonists on cytokine-induced production of thymic stromal lymphopoietin (TSLP), an indispensable cytokine in the development of allergic diseases, by lung tissue cells. Methods: Normal human bronchial epithelial cells (NHBE), smooth muscle cells (BSMC) and fibroblasts (NHLF) were stimulated with the IL-4 and TNF-α cytokines, alone and in combination, and their production of TSLP was examined by ELISA. The effects of β₂- agonists (salmeterol, formoterol, salbutamol), intracellular cyclic adenosine monophosphate (cAMP)-elevating agents (8-bromo-cAMP, dibutyryl cAMP, forskolin) and a corticosteroid (fluticasone) on the cytokine-induced TSLP production were examined. Results: The following results were observed in all three types of lung tissue cells tested (that is, NHBE, BSMC and NHLF). Costimulation with IL-4 and TNF-α significantly induced TSLP production, and β₂- agonists further enhanced it via upregulation of intracellular cAMP. However, addition of a corticosteroid to the cytokines and β₂-agonist resulted in a marked decrease in TSLP production. Conclusions: β₂-Agonists significantly enhanced the cytokine-induced TSLP production by primary human lung tissue cells. This may be partly responsible for the undesirable clinical effects of continuous β₂-agonist monotherapy, and combination therapy with a corticosteroid might effectively inhibit TSLP-mediated allergic inflammation.