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

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Presentation on theme: "Deficient glucocorticoid induction of anti-inflammatory genes in nasal polyp fibroblasts of asthmatic patients with and without aspirin intolerance  Laura."— Presentation transcript:

1 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 e12 (November 2013) DOI: /j.jaci Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

2 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  , e12DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

3 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  , e12DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

4 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  , e12DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

5 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  , e12DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

6 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  , e12DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

7 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  , e12DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

8 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  , e12DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

9 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  , e12DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

10 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  , e12DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

11 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  , e12DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

12 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  , e12DOI: ( /j.jaci ) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

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