Inhibition of signal transducer and activator of transcription 1 attenuates allergen-induced airway inflammation and hyperreactivity

• Published in: Journal of allergy and clinical immunology 2004-08, Vol.114 (2), p.288-295
• Main Authors: Quarcoo, David, Weixler, Silke, Groneberg, David, Joachim, Ricarda, Ahrens, Birgit, Wagner, Andreas H., Hecker, Markus, Hamelmann, Eckard
• Format: Article
• Language: English
• Subjects: Allergens - immunology; Animals; Asthma; Asthma - drug therapy; Biological and medical sciences; bronchial hyperreactivity; Bronchial Hyperreactivity - drug therapy; Bronchoalveolar Lavage Fluid - chemistry; CD40; CD40 Antigens - physiology; Cell adhesion & migration; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - genetics; Female; Fluorescent Antibody Technique; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene expression; Immunopathology; Interleukin-5 - analysis; Interleukin-5 - genetics; Kinases; Medical sciences; Mice; Mice, Inbred BALB C; Oligonucleotides, Antisense - therapeutic use; RNA, Messenger - analysis; Rodents; STAT1 Transcription Factor; Trans-Activators - antagonists & inhibitors; Trans-Activators - genetics; vascular cell adhesion molecule 1; Vascular Cell Adhesion Molecule-1 - analysis
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2004.03.055

Transcriptional factors of the signal transducer and activator of transcription (STAT) family play an important role in orchestrating immune reactions. The aim of the current study was to investigate the role of STAT-1 in murine allergen–induced sensitization and development of airway inflammation (AI) and airway hyperreactivity (AHR), cardinal features of bronchial asthma. BALB/c mice were systemically sensitized to ovalbumin and challenged with ovalbumin through the airways. Decoy oligonucleotide (ODN) specific for STAT-1 was applied once locally to the airways of sensitized animals before allergen airway challenges. Single application of decoy ODN markedly and significantly reduced numbers of eosinophils and lymphocytes in bronchoalveolar lavage fluids compared with those seen in sensitized and challenged animals receiving mutant control ODN. Associated with this decrease in eosinophilic AI were significantly reduced levels of IL-5 in BAL fluid, of CD40 expression in peribronchial infiltrates, and of vascular cell adhesion molecule 1 expression in vascular endothelial cells, respectively. In addition, development of AHR after allergen sensitization and airway challenges was effectively abolished after local STAT-1 decoy ODN treatment. The data indicate that a decoy ODN neutralizing STAT-1 effectively inhibits allergen-induced AI and AHR, probably by attenuating upregulation of costimulatory and adhesion molecules, and suggest a significant role of STAT-1 in asthma pathology.