Impaired translation of CCAAT/enhancer binding protein a mRNA in bronchial smooth muscle cells of asthmatic patients

• Published in: Journal of allergy and clinical immunology Vol. 123; no. 3; pp. 639 - 645
• Main Authors: BORGER, Peter, MIGLINO, Nicola, BARAKET, Melissa, BLACK, Judith L, TAMM, Michael, ROTH, Michael
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier 01.03.2009; Elsevier Limited
• Subjects: Asthma; Biological and medical sciences; Chronic obstructive pulmonary disease, asthma; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene expression; Genotype & phenotype; Immunopathology; Kinases; Medical sciences; Pathology; Peptides; Pneumology; Proteins; Rodents; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Smooth muscle; Human; Lung disease; Immunopathology; C/EBPα; Respiratory disease; Hyperplasia; Bronchus; Smooth muscle; bronchial smooth muscle cell hyperplasia; Respiratory system; Genetic translation; Asthma; C/EBP transcription factor; Myocyte; messenger RNA translation; Respiratory tract; Binding protein; Immunology; Messenger RNA; Bronchus disease; Obstructive pulmonary disease
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2008.11.006

Background Bronchial smooth muscle (BSM) cells of asthmatic patients have an impaired expression of CCAAT/enhancer binding protein (C/EBP) α, which is associated with increased proliferation. Objective We sought to assess the translational regulation ofCEBPAmRNA in cultured BSM cells of healthy control subjects (n = 11) and asthmatic patients (n = 12). Methods Translation efficiency was studied by using a translation control reporter system driven by the control elements present in theCEBPAmRNA. Translation efficiency was determined by the ratio of 2 artificial hemagglutinin (HA.11) proteins: p23 and p12. We also analyzed levels of proteins that control translation ofCEBPAmRNA, namely heterogeneous nuclear ribonucleoprotein E2, calreticulin, eukaryotic translation initiation factor (eIF4E), and 4E binding protein. Results Compared with healthy control subjects, BSM cells of asthmatic patients proliferate faster (2.1-fold) and are primed for IL-6 secretion. Real-time RT-PCR showed that BSM cells of asthmatic patients express normal levels ofCEBPAmRNA, whereas they express lower levels of C/EBPα (p42). Transient transfections with the translation control reporter system construct showed a disturbed p12/p23 ratio in BSM cells of asthmatic patients relative to healthy control subjects, which coincided with lower levels of eIF4E. Conclusion BSM cells of asthmatic patients have normal levels ofCEBPAmRNA but inadequately reinitiate the translation into C/EBPα. Impaired translation control upstream of eIF4E might underlie the observed increased proliferation and priming of BSM cells of asthmatic patients.