Disease-specific expression and regulation of CCAAT/enhancer-binding proteins in asthma and chronic obstructive pulmonary disease Peter Borger, PhD,

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Presentation transcript:

Disease-specific expression and regulation of CCAAT/enhancer-binding proteins in asthma and chronic obstructive pulmonary disease Peter Borger, PhD, Hisako Matsumoto, PhD, Sarah Boustany, Mikael M.C. Gencay, PhD, Janette K. Burgess, PhD, Greg G. King, MD, Judith L. Black, PhD, MBBS, FRACP, Michael Tamm, MD, Michael Roth, PhD Journal of Allergy and Clinical Immunology Volume 119, Issue 1, Pages 98-105 (January 2007) DOI: 10.1016/j.jaci.2006.07.056 Copyright © 2007 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 A, Histology and immunohistochemistry of C/EBPα of bronchial tissue sections. Top panel, Routine histologic examination of nonasthmatic and asthmatic airway sections demonstrates an increase in the size of the BSMC layer (hematoxylin and eosin staining, original magnification ×160). Middle panel, Immunohistochemical staining with a C/EBPα-specific antibody detected with fluorescein isothiocyanate–labeled secondary antibody. Bottom panel, Staining with the secondary antibody demonstrates the specificity of the signal. ASM, airway smooth muscle. B, Immunohistochemistry of C/EBPα in bronchial tissue sections. Sections were obtained and immunohistochemistry was performed as described in the Methods section. Lung sections from a healthy individual and an asthmatic patient were stained in parallel with a specific C/EBPα antibody by using peroxidase-based immunohistochemical staining. Mayer's hematoxylin was used for counterstaining. Tissue sections were mounted with 60% glycerol in PBS and examined by means of light microscopy. Arrows indicate ASM bundles. C, Expression patterns of C/EBPα, β, δ, and ε in cultured BSMCs. BSMCs were cultured from lung specimens of healthy subjects, asthmatic patients, and patients with COPD (as indicated). Staining was performed with antibodies specific for C/EBPα, β, δ, and ε according to the procedure described in the Methods section. The figure is representative of 3 independent immunohistochemical staining experiments. Journal of Allergy and Clinical Immunology 2007 119, 98-105DOI: (10.1016/j.jaci.2006.07.056) Copyright © 2007 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Immunoanalysis of C/EBPα, β, δ, and ε in cultured BSMCs. The expression of the distinct C/EBPs is variable per cell line. The upper and lower panels represent the 2 most extreme protein expression patterns of C/EBPα (A), C/EBPβ (B), C/EBPδ (C), and C/EBPε (D) observed in whole-cell lysates of cultured BSMCs of 9 healthy control subjects, 12 asthmatic patients, and 10 patients with end-stage COPD (emphysema). BSMCs were cultured in the presence or absence of 5% FBS (as indicated). The C/EBP protein expression data of all cell lines are summarized in Table I. Journal of Allergy and Clinical Immunology 2007 119, 98-105DOI: (10.1016/j.jaci.2006.07.056) Copyright © 2007 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 C/EBPα mRNA expression in BSMC lines of a healthy control subject and 2 asthmatic patients. RT-PCR products (top) and protein (bottom) in BSMCs obtained from 1 control cell line cultured from a nonasthmatic individual (NA) and 2 cell lines cultured from 2 asthmatic subjects, 1 negative (A1) and 1 positive (A2) for C/EBPα protein expression, are shown. Cells were cultured in the absence or presence of 5% FBS (as indicated). Journal of Allergy and Clinical Immunology 2007 119, 98-105DOI: (10.1016/j.jaci.2006.07.056) Copyright © 2007 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Representative EMSAs demonstrating C/EBP DNA-binding and supershift analysis with antibodies for C/EBPδ, C/EBPβ, and C/EBPδ+ε. Nuclear extracts were obtained from BSMC lines cultured from tissue of a healthy control subject and an asthmatic patient (A) and a healthy control subject and a patient with COPD (B). The data shown are representative of 3 independent experiments. Journal of Allergy and Clinical Immunology 2007 119, 98-105DOI: (10.1016/j.jaci.2006.07.056) Copyright © 2007 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Effects of budesonide or formoterol alone and a combination of both drugs on C/EBP protein expression. BSMCs were obtained from control subjects (left panel), patients with COPD (middle panel), and asthmatic subjects (right panel) who expressed alternatively sized C/EBPα (middle right) or do not express C/EBPα (left panel). BSMCs were cultured without FBS, with 5% FBS, with budesonide (10−8 M), with formoterol (10−8 M), and with a combination of budesonide and formoterol (10−8 M). The data shown are representative of 5 independent experiments. Journal of Allergy and Clinical Immunology 2007 119, 98-105DOI: (10.1016/j.jaci.2006.07.056) Copyright © 2007 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Schematic representation of the putative involvement of C/EBP proteins in the tissue-remodeling process. C/EBPα inhibits proliferation in most cells, including respiratory tissue cells, and functions as a brake for cell-cycle progression. Decreased levels of C/EBPα, as observed in the asthma group, might shift the balance in favor of increased proliferation and could potentially explain the remodeling in the asthmatic airway. On the other hand, diminished expression of the cell-cycle accelerator C/EBPδ might lead to lung tissue loss. Journal of Allergy and Clinical Immunology 2007 119, 98-105DOI: (10.1016/j.jaci.2006.07.056) Copyright © 2007 American Academy of Allergy, Asthma & Immunology Terms and Conditions