Inhaled long-acting β2 agonists enhance glucocorticoid receptor nuclear translocation and efficacy in sputum macrophages in COPD Rubaiyat Haque, MBBS,

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Inhaled long-acting β2 agonists enhance glucocorticoid receptor nuclear translocation and efficacy in sputum macrophages in COPD Rubaiyat Haque, MBBS, Amir Hakim, PhD, Thunicia Moodley, PhD, Alfonso Torrego, MD, Sarah Essilfie-Quaye, PhD, Elen Jazrawi, BSc, Malcolm Johnson, PhD, Peter J. Barnes, FRS, FMedSci, Ian M. Adcock, PhD, FSB, Omar Sharif Usmani, MBBS, PhD Journal of Allergy and Clinical Immunology Volume 132, Issue 5, Pages 1166-1173 (November 2013) DOI: 10.1016/j.jaci.2013.07.038 Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Validation of the quality of nuclear extract and GR-GRE binding. The quality of nuclear extracts (A) was determined by using Western blotting. FP-induced GR-GRE binding (B) and FP-induced GR nuclear localization (C) were assessed in U937 monocytes. Results represent the mean ± SEM of 3 independent experiments. *P < .05 denotes statistical significance versus untreated cells. TATA BP, TATA-binding protein. Journal of Allergy and Clinical Immunology 2013 132, 1166-1173DOI: (10.1016/j.jaci.2013.07.038) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Confocal laser images of GR subcellular localization in sputum macrophages following corticosteroid (FP 500 μg) treatment. A and D, 4’, 6-diamidino-2-phenylindole dihydrochloride (DAPI) staining (blue channel). B and E, Cytoplasmic and nuclear GR immunostaining (green channel). C and F, Overlay of A and B. Journal of Allergy and Clinical Immunology 2013 132, 1166-1173DOI: (10.1016/j.jaci.2013.07.038) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Effect of inhaled SLM and FP on GR-GRE binding in nuclear extracts from induced sputum macrophages (A) and PBMCs (B). Mean ± SEM absorbance values of GR-GRE binding are shown 60 minutes postinhalation of treatment, where numeric values are inhaled drug doses in micrograms. n = 8 subjects. *P < .05 and **P < .01 denote statistical significance between treatments. Journal of Allergy and Clinical Immunology 2013 132, 1166-1173DOI: (10.1016/j.jaci.2013.07.038) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Effect of FP (10−9 mol/L) and SLM (10−7 mol/L) on GR-GRE DNA binding in sputum macrophages from patients with COPD ex vivo. Mean ± SEM absorbance values of GR-GRE binding are shown. n = 5 subjects. *P < .05 denotes statistical significance between treatments. Journal of Allergy and Clinical Immunology 2013 132, 1166-1173DOI: (10.1016/j.jaci.2013.07.038) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Effect of FP (10−9 mol/L) and SLM (10−8 mol/L) on MKP-1 mRNA induction and GRE-luciferase activity in macrophage-like PMA-treated U937 cells in vitro. A, MKP-1 mRNA expression normalized with GAPDH (Fig 5, A) and the fold-increase in GR of stimulated versus nonstimulated cells (B) are shown. Results represent the mean ± SEM of 3 independent experiments. *P < .05 and ***P < .001 denote statistical significance between treatments. GAPDH, Glyceraldehyde 3-phosphate dehydrogenase. Journal of Allergy and Clinical Immunology 2013 132, 1166-1173DOI: (10.1016/j.jaci.2013.07.038) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Effect of FP and SLM on IL-1β–induced CXCL8 in macrophage-like U937 cells. Results represent the mean ± SEM of 8 independent experiments. *P < .05 denotes statistical significance versus FP (10−11 mol/L) and #P < .01 denotes statistical significance versus IL-1β–stimulated. Journal of Allergy and Clinical Immunology 2013 132, 1166-1173DOI: (10.1016/j.jaci.2013.07.038) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions