Mucin 1 downregulation associates with corticosteroid resistance in chronic rhinosinusitis with nasal polyps Javier Milara, PhD, PharmD, Teresa Peiró,

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Mucin 1 downregulation associates with corticosteroid resistance in chronic rhinosinusitis with nasal polyps Javier Milara, PhD, PharmD, Teresa Peiró, PhD, Miquel Armengot, PhD, MD, Soledad Frias, MD, Anselm Morell, Adela Serrano, PhD, Julio Cortijo, PhD Journal of Allergy and Clinical Immunology Volume 135, Issue 2, Pages 470-476 (February 2015) DOI: 10.1016/j.jaci.2014.07.011 Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 MUC1 expression is downregulated in patients with NP-CR. mRNA expression of MUC1 in NP tissue of patients with NPwA (n = 12), NP-ATA (n = 8), NP-AIA (n = 34), and NP-CR (n = 19) before (red color) and after (black color) oral corticosteroid treatment (A). Data are expressed as 2−ΔCt mRNA MUC1 levels normalized to GAPDH mRNA levels. Western blotting analysis of MUC1-CT protein expression of patients with NPwA, NP-ATA, NP-AIA, and NP-CR (B). Representative Western blot results are shown. Data are expressed as MUC1-CT protein levels as determined by densitometry relative to β-actin levels. Box plot representing the composite score of the MUC1-CT marker across NP (C). NPs were immunostained for MUC1-CT (brown) and counterstained with hematoxylin (D). Representative immunohistochemistry images are shown. Scale bar = 50 μm. Data are presented as a box and whisker plot of medians, interquartile range (IQR), and minimum and maximum values. P values were obtained by the Kruskal-Wallis test followed by Dunn post-hoc test. Journal of Allergy and Clinical Immunology 2015 135, 470-476DOI: (10.1016/j.jaci.2014.07.011) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 NP epithelial cells from patients with NP-CR are insensitive to dexamethasone. Primary NP epithelial cells obtained from patients with NPwA (A and C) (n = 4) and NP-CR (B and D) (n = 4) were incubated with or without 1 μM dexamethasone for 2 hours before LPS (1 μg/mL) or flagellin (Flag; 1 μg/mL) stimulation for 24 hours. The IL-8 (A and B) and GM-CSF (C and D) concentrations were measured by ELISA. Results are expressed as means (SEM) of 3 independent experiments in each population. Two-way ANOVA was followed by the post-hoc Bonferroni test. *P < .05 related to control release in the same subject group; #P < .05 related to the stimulus LPS or Flag. Journal of Allergy and Clinical Immunology 2015 135, 470-476DOI: (10.1016/j.jaci.2014.07.011) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 MUC1-CT is coexpressed with GRα to form a complex that translocates to the nucleus following dexamethasone stimulation. The nuclear, cytoplasmic, or total protein immunoprecipitates (IP) of GRα or MUC1-CT were collected from Beas-2B cells incubated in the presence or absence (basal) of dexamethasone (Dex; 1 μM) for 4 hours (A). IP were immunoblotted (IB) with opposite antibodies MUC1-CT or GRα or with the same antibodies used for immunoprecipitation as controls. The IgG isotype was used as a negative control for immunoprecipitation. Histone H3 and myosin IIa antibodies were used in Western blots of various subcellular and total protein extracts to determine the specificity of subcellular protein extraction. NP tissues from NPwA (n = 6) and NP-CR (n = 7) were lysed and immunoprecipitated with GRα or MUC1-CT antibodies (B). Opposite antibodies were probed with IB to analyze MUC1-CT-GRα complex expression variations and the same antibodies as controls. The IgG isotype was used as a negative control for immunoprecipitation. Representative Western blots are shown. Graphs represent the densitometry of ratios to GRα or MUC1-CT protein levels as appropriate. Results are expressed as means (SEM) of 3 independent experiments. One-way ANOVA was followed by the post-hoc Bonferroni test. *P < .05 related to basal (A) or NPwA (B) group. Journal of Allergy and Clinical Immunology 2015 135, 470-476DOI: (10.1016/j.jaci.2014.07.011) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Journal of Allergy and Clinical Immunology 2015 135, 470-476DOI: (10.1016/j.jaci.2014.07.011) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Journal of Allergy and Clinical Immunology 2015 135, 470-476DOI: (10.1016/j.jaci.2014.07.011) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Journal of Allergy and Clinical Immunology 2015 135, 470-476DOI: (10.1016/j.jaci.2014.07.011) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Journal of Allergy and Clinical Immunology 2015 135, 470-476DOI: (10.1016/j.jaci.2014.07.011) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 Journal of Allergy and Clinical Immunology 2015 135, 470-476DOI: (10.1016/j.jaci.2014.07.011) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E6 Journal of Allergy and Clinical Immunology 2015 135, 470-476DOI: (10.1016/j.jaci.2014.07.011) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E7 Journal of Allergy and Clinical Immunology 2015 135, 470-476DOI: (10.1016/j.jaci.2014.07.011) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E8 Journal of Allergy and Clinical Immunology 2015 135, 470-476DOI: (10.1016/j.jaci.2014.07.011) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E9 Journal of Allergy and Clinical Immunology 2015 135, 470-476DOI: (10.1016/j.jaci.2014.07.011) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions