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Published ahead of print on April 28, 2005, doi:10.1164/rccm.200408-1041OC
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American Journal of Respiratory and Critical Care Medicine Vol 172. pp. 704-712, (2005)
© 2005 American Thoracic Society
doi: 10.1164/rccm.200408-1041OC

Glucocorticoid Receptor Nuclear Translocation in Airway Cells after Inhaled Combination Therapy

Omar S. Usmani, Kazuhiro Ito, Kittipong Maneechotesuwan, Misako Ito, Malcolm Johnson, Peter J. Barnes and Ian M. Adcock

Airways Disease Section, National Heart and Lung Institute, Imperial College London, London, United Kingdom

Correspondence and requests for reprints should be addressed to Professor Ian M. Adcock, Ph.D., Airways Disease Section, National Heart and Lung Institute, Imperial College London, Dovehouse Street, London SW3 6LY, UK. E-mail address: ian.adcock{at}imperial.ac.uk

Clinical evidence is accumulating for the efficacy of adding inhaled long-acting ß2-agonists (LABAs) to corticosteroids in asthma. Corticosteroids bind to cytoplasmic glucocorticoid receptors (GRs), which then translocate to the nucleus where they regulate gene expression. This article reports the first evidence in vivo of an interaction between inhaled LABA and corticosteroid on GR nuclear translocation in human airway cells using immunocytochemistry. We initially demonstrated significant GR activation 60 minutes after inhalation of 800 µg beclomethasone dipropionate in six healthy subjects. Subsequently, we determined the effects of salmeterol and fluticasone propionate (FP) in seven steroid-naive patients with asthma. We observed dose-dependent GR activation with 100- and 500-µg doses of FP, and to a lesser extent with 50 µg salmeterol alone. However, combination therapy with 100 µg FP and salmeterol augmented the action of FP on GR nuclear localization. In vitro, salmeterol enhanced FP effects on GR nuclear translocation in epithelial and macrophage-like airway cell lines. In addition, salmeterol in combination with FP enhanced glucocorticoid response element (GRE)–luciferase reporter gene activity and mitogen-activated protein kinase phosphatase 1 (MKP-1) and secretory leuko-proteinase inhibitor (SLPI) gene induction. Together, our data confirm that GR nuclear translocation may underlie the complementary interactions between LABAs and corticosteroids, although the precise signal transduction mechanisms remain to be determined.

Key Words: asthma • human • lung • therapy • transcription factors




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