TY - JOUR T1 - Corticosteroid-dependent transcription is reduced by inflammatory stimuli in human airway epithelial cells: Rescue by long-acting β<sub>2</sub>-adrenoceptor agonists JF - European Respiratory Journal JO - Eur Respir J VL - 38 IS - Suppl 55 SP - 1448 AU - Christopher Rider AU - Elizabeth King AU - Neil Holden AU - Mark Giemmbycz AU - Robert Newton Y1 - 2011/09/01 UR - http://erj.ersjournals.com/content/38/Suppl_55/1448.abstract N2 - Rationale: Inhaled corticosteroids (glucocorticoids) are the most effective treatment for inflammatory diseases such as asthma. However, in some patients with severe disease, or who smoke, or suffer from COPD, these drugs are less effective. While many investigators focus on the repression of inflammatory gene expression, corticosteroids also induce the expression (transactivation) of numerous genes to elicit anti-inflammatory effects.Results: Using human bronchial airway epithelial, BEAS-2B, and pulmonary, A549, cells, we show that tumour necrosis factor (TNF) α, interleukin (IL)-1β, fetal calf serum (FCS), phorbol ester, cigarette smoke extract and a Gq-linked G-protein coupled receptor agonist, all attenuate simple glucocorticoid response element (GRE)-dependent transcription. With TNFα and FCS, this was not overcome by increasing concentrations of dexamethasone, budesonide or fluticasone propionate. Thus, maximal GRE-dependent transcription was reduced and this was confirmed for the glucocorticoid-induced gene, p57KIP2. Long-acting β2-adrenoceptor agonists (LABAs), formoterol fumarate and salmeterol xinafoate, enhanced simple GRE-dependent transcription to a level that could not be achieved by glucocorticoid alone. In the presence of TNFα or FCS, which repressed corticosteroid responsiveness, LABAs restored corticosteroid-dependent transcription to that achieved by corticosteroid alone.Conclusions: The repression of transactivation represents a mechanism to explain corticosteroid resistance and its reversal may explain the clinical benefit of LABAs as an add-on therapy in asthma and COPD.Funded by AstraZeneca. ER -