Glucocorticoid receptor nuclear translocation in airway cells after inhaled combination therapy.
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. 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 microg 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-microg doses of FP, and to a lesser extent with 50 microg salmeterol alone. However, combination therapy with 100 microg 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.
Usmani
Omar S
OS
Airways Disease Section, National Heart and Lung Institute, Imperial College London, Dovehouse Street, London SW3 6LY, UK.
Ito
Kazuhiro
K
Maneechotesuwan
Kittipong
K
Ito
Misako
M
Johnson
Malcolm
M
Barnes
Peter J
PJ
Adcock
Ian M
IM
D000305:Adrenal Cortex Hormones / Q000627:therapeutic use; D000318:Adrenergic beta-Agonists / Q000494:pharmacology / Q000627:therapeutic use; D000328:Adult; D000420:Albuterol / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000730:Androstadienes / Q000494:pharmacology / Q000627:therapeutic use; D018927:Anti-Asthmatic Agents / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy* / Q000378:metabolism*; D001507:Beclomethasone / Q000627:therapeutic use; D001692:Biological Transport / Q000187:drug effects; D001993:Bronchodilator Agents / Q000494:pharmacology / Q000627:therapeutic use; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D004359:Drug Therapy, Combination; D054638:Dual Specificity Phosphatase 1; D005260:Female; D000068298:Fluticasone; D017930:Genes, Reporter; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism; D008156:Luciferases / Q000235:genetics; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D020218:Response Elements; D000068299:Salmeterol Xinafoate; D053481:Secretory Leukocyte Peptidase Inhibitor; D013183:Sputum / Q000166:cytology; D014158:Transcription, Genetic / Q000187:drug effects
D000305:Adrenal Cortex Hormones; D000318:Adrenergic beta-Agonists; D000730:Androstadienes; D018927:Anti-Asthmatic Agents; D001993:Bronchodilator Agents; D018797:Cell Cycle Proteins; D017874:Immediate-Early Proteins; D053491:Proteinase Inhibitory Proteins, Secretory; D011506:Proteins; D011965:Receptors, Glucocorticoid; C506814:SLPI protein, human; D053481:Secretory Leukocyte Peptidase Inhibitor; D000068299:Salmeterol Xinafoate; D000068298:Fluticasone; D008156:Luciferases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; C517019:DUSP1 protein, human; D054638:Dual Specificity Phosphatase 1; D017027:Protein Tyrosine Phosphatases; D001507:Beclomethasone; D000420:Albuterol