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

Quarcoo, David; Weixler, Silke; Groneberg, David; Joachim, Ricarda; Ahrens, Birgit; Wagner, Andreas H.; Hecker, Markus; Hamelmann, Eckard

doi:10.1016/j.jaci.2004.03.055

« Previous Next »The Journal of Allergy and Clinical Immunology
Volume 114, Issue 2 , Pages 288-295, August 2004

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

From ^athe Department of Pediatric Pneumology and Immunology and ^bthe Department of Internal Medicine, Charité-Humboldt University, Berlin, and ^cthe Department of Cardiovascular Physiology, University of Göttingen, Göttingen, Germany

Received 22 October 2003; received in revised form 10 March 2004; accepted 18 March 2004.

Berlin and Göttingen, Germany

Abstract

Background

Transcriptional factors of the signal transducer and activator of transcription (STAT) family play an important role in orchestrating immune reactions.

Objective

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.

Methods

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.

Results

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.

Conclusion

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.

Keywords: CD40, vascular cell adhesion molecule 1, asthma, bronchial hyperreactivity

Abbreviations: AHR, Airway hyperreactivity, AI, Airway inflammation, APC, Antigen-presenting cell, BALF, Bronchoalveolar lavage fluid, CD40L, CD40 ligand, ODN, Oligonucleotide, OVA, Ovalbumin, STAT, Signal transducer and activator of transcription, VCAM, Vascular cell adhesion molecule