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Published ahead of print on April 28, 2005, doi:10.1164/rccm.200408-1041OC

Am. J. Respir. Crit. Care Med., Volume 172, Number 6, September 2005, 704-712

A more recent version of this article appeared on September 15, 2005
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Submitted on August 12, 2004
Accepted on April 25, 2005

Glucocorticoid Receptor Nuclear Translocation in Airway Cells Following Inhaled Combination Therapy

Omar S Usmani1, Kazuhiro Ito1, Kittipong Maneechotesuwan1, Misako Ito1, Malcolm Johnson1, Peter J Barnes1, and Ian M Adcock1*

1 Airways Disease Section, National Heart and Lung Institute, Imperial College London, London, UK

* To whom correspondence should be addressed. E-mail: ian.adcock{at}imperial.ac.uk.

Clinical evidence is accumulating for the efficacy of adding inhaled long-acting {beta}2-agonists (LABAs) to corticosteroids in asthma. Corticosteroids bind to cytoplasmic glucocorticoid receptors (GRs), which then translocate to the nucleus where they regulate gene expression. Here we report 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 following inhalation of 800µg beclomethasone dipropionate in six healthy subjects. Subsequently, we determined the effects of salmeterol and fluticasone propionate (FP) in seven steroid-naive asthmatics. We observed dose-dependent GR activation with FP 100µg and 500µg doses, and to a lesser extent with salmeterol 50µg alone. However, combination therapy with FP 100µg 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: Transcription Factors, Human, Lung, Asthma, Therapy




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