Deficient glucocorticoid induction of anti-inflammatory genes in nasal polyp fibroblasts of asthmatic patients with and without aspirin intolerance Laura.

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Deficient glucocorticoid induction of anti-inflammatory genes in nasal polyp fibroblasts of asthmatic patients with and without aspirin intolerance Laura Fernández-Bertolín, MS, Joaquim Mullol, MD, PhD, Mireya Fuentes-Prado, BS, Isam Alobid, MD, PhD, Jordi Roca-Ferrer, PhD, César Picado, MD, PhD, Laura Pujols, PhD Journal of Allergy and Clinical Immunology Volume 132, Issue 5, Pages 1243-1246.e12 (November 2013) DOI: 10.1016/j.jaci.2013.07.010 Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Effect of dexamethasone on MKP-1, GILZ, and TTP expression. A, RT-PCR analysis of nasal mucosa (NM; n = 10) and nasal polyp fibroblasts from aspirin-tolerant (ATA-NP; n = 5) and aspirin-intolerant (AIA-NP; n = 7) asthmatic patients. B, Immunoblot analysis of nasal mucosa (n = 5) and nasal polyp (NP; n = 5) fibroblasts. Fibroblasts were incubated with dexamethasone (10−7 mol/L) for the indicated times. *P < .05 versus untreated/0 hour. †P < .05 versus NM. Journal of Allergy and Clinical Immunology 2013 132, 1243-1246.e12DOI: (10.1016/j.jaci.2013.07.010) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Relationship between H4 K5 acetylation or IL-8 inhibition and the expression of MKP-1 and GILZ mRNAs induced by dexamethasone. H4 K5 acetylation levels (A) and the IC50 values for IL-8 inhibition (B) after 1 hour and 24 hours, respectively, of dexamethasone treatment are plotted against MKP-1/GILZ mRNA levels after 2 hours (MKP-1) and 6 hours (GILZ) of dexamethasone treatment. Regression lines with 95% CIs are shown. DEX, Dexamethasone. Journal of Allergy and Clinical Immunology 2013 132, 1243-1246.e12DOI: (10.1016/j.jaci.2013.07.010) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Basal expression of GRα and GRβ. A, GRα and GRβ mRNA quantification by RT-PCR. B, GRα and GRβ protein quantification in total (GRα) and nuclear (GRβ) extracts from nasal mucosa (n = 10) and nasal polyp (n = 12) fibroblasts. Images show representative immunoblots from 4 nasal mucosa and 4 nasal polyp fibroblast lines. The lower band detected in GRβ immunoblots is a nonspecific product. NS, Nonsignificant. Journal of Allergy and Clinical Immunology 2013 132, 1243-1246.e12DOI: (10.1016/j.jaci.2013.07.010) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Effect of dexamethasone on GR nuclear translocation. A, B, Immunofluorescence analysis of GRα nuclear translocation in dexamethasone (10−7 mol/L)-treated nasal mucosa (NM, n = 10) and nasal polyp (NP, n = 12) fibroblasts for the indicated times. C, D, Immunoblot analysis of GRα/GRβ nuclear translocation in nasal mucosa (n = 9, white boxes) and nasal polyp (n = 8, gray boxes) fibroblasts. NS, Nonsignificant. *P < .05 versus 0 hour. Journal of Allergy and Clinical Immunology 2013 132, 1243-1246.e12DOI: (10.1016/j.jaci.2013.07.010) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Basal expression of MKP-1, GILZ, and TTP. A, Target RT-PCR mRNA quantification in nasal mucosa (n = 10) and nasal polyp fibroblasts from aspirin-tolerant (ATA-NP; n = 5) and aspirin-intolerant (AIA-NP; n = 7) asthmatic patients. *P < .05 versus nasal mucosa. B, Target protein expression in nasal mucosa and nasal polyp fibroblasts (n = 6). C, Representative TTP immunoblot of 10−7 mol/L dexamethasone (DEX)-treated nasal mucosa fibroblasts. Journal of Allergy and Clinical Immunology 2013 132, 1243-1246.e12DOI: (10.1016/j.jaci.2013.07.010) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Mechanisms of dexamethasone-mediated induction of MKP-1, GILZ, and TTP mRNAs. Target RT-PCR analysis of nasal mucosa fibroblasts (n = 4) incubated with RU486 (A), actinomycin D (Act D, B and D), or cycloheximide (CHX, C), plus 10−7 mol/L dexamethasone (DEX) for 2 hours (MKP-1 and TTP, Fig E4, A-C), 6 hours (GILZ, Fig E4, A-C), or the indicated times (Fig E4, D). *P < .05 versus untreated cells. †P < .05. Journal of Allergy and Clinical Immunology 2013 132, 1243-1246.e12DOI: (10.1016/j.jaci.2013.07.010) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 Effect of dexamethasone on MKP-1 and GILZ proteins. Representative immunoblot images of MKP-1 (A) and GILZ (B) proteins from nasal mucosa (n = 5) and nasal polyp (n = 5) fibroblasts incubated with dexamethasone (10−7 mol/L) for the indicated times (see quantification in Fig 1, B). The upper band detected in MKP-1 immunoblots is a nonspecific product. Journal of Allergy and Clinical Immunology 2013 132, 1243-1246.e12DOI: (10.1016/j.jaci.2013.07.010) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E6 Effect of dexamethasone on MKP-1, GILZ, and TTP expression. Target RT-PCR analysis of nasal mucosa (NM; n = 7) and nasal polyp (NP; n = 7) fibroblasts treated with the indicated dexamethasone concentrations for 2 hours (upper and lower graphs) and 6 hours (middle graph). *P < .05 versus nasal mucosa. The mean EC50 is shown. NS, Nonsignificant. Journal of Allergy and Clinical Immunology 2013 132, 1243-1246.e12DOI: (10.1016/j.jaci.2013.07.010) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E7 Basal and dexamethasone-induced H4 K5 acetylation. Acetylated H4 K5 immunoblot of nasal mucosa (NM; n = 7) and nasal polyp (NP; n = 7) fibroblasts at baseline (A) and after incubation with dexamethasone (10−7 mol/L) for the indicated times (B). NS, Nonsignificant. *P < .05 compared with 0 hour. Journal of Allergy and Clinical Immunology 2013 132, 1243-1246.e12DOI: (10.1016/j.jaci.2013.07.010) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E8 Effect of dexamethasone on GRα binding to GILZ and MKP-1 promoters. Nasal mucosa (white bars) and nasal polyp (gray bars) fibroblasts were incubated with dexamethasone (10−7 mol/L) for the indicated times (n = 4). Chromatin immunoprecipitation was performed with an anti-GR antibody, and GILZ (A) and MKP-1 promoters (B) were amplified by using PCR. NA, Samples with no antibody added. *P < .05 versus 0 hour. †P < .05. Journal of Allergy and Clinical Immunology 2013 132, 1243-1246.e12DOI: (10.1016/j.jaci.2013.07.010) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E9 Effect of dexamethasone on IL-8 secretion. A, IL-8 quantification in nasal mucosa (NM, n = 10) and nasal polyp (NP, n = 12) fibroblasts treated with 10% FBS-supplemented medium (C) and the indicated dexamethasone concentrations for 24 hours. B, Individual and median IC50 values from Fig E9, A, are plotted. Journal of Allergy and Clinical Immunology 2013 132, 1243-1246.e12DOI: (10.1016/j.jaci.2013.07.010) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions