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Small Interfering RNA against Transcription Factor STAT6 Inhibits Allergic Airway Inflammation and Hyperreactivity in Mice¹

Yasemin Darcan-Nicolaisen^*, Holger Meinicke^*, Gabriele Fels^*, Olga Hegend, Annekathrin Haberland, Anja Kühl, Christoph Loddenkemper, Martin Witzenrath, Stefanie Kube, Wolfgang Henke and Eckard Hamelmann^2,*,¶

^* Department of Pediatric Pneumology and Immunology, Department of Otorhinolaryngology, Department of Pathology, Research Center ImmunoSciences, and Department of Internal Medicine, Infectious and Respiratory Diseases, Charité University Medicine, Berlin, and the ^¶ University Children’s Hospital, Ruhr-University, Bochum, Germany

In the context of allergic immune responses, activation of STAT6 is pivotal for Th2-mediated IgE production and development of airway inflammation and hyperreactivity. We analyzed whether gene silencing of STAT6 expression by RNA interference was able to suppress allergen-induced immune and airway responses. Knockdown effectiveness of three different STAT6 siRNA molecules was analyzed in murine and human cell cultures. The most potent siRNA was used for further testing in a murine model of allergen-induced airway inflammation and airway hyperreactivity (AHR). BALB/c mice were sensitized with OVA/alum twice i.p. (days 1 and 14), and challenged via the airways with allergen (days 28–30). Intranasal application of STAT6 siRNA before and during airway allergen challenges reduced levels of infiltrating cells, especially of eosinophils, in the bronchoalveolar lavage fluid, compared with GFP siRNA-treated sensitized and challenged controls. Allergen-induced alterations in lung tissues (goblet cell hyperplasia, peribronchial inflammation with eosinophils and CD4 T cells) were significantly reduced after STAT6 siRNA treatment. Associated with decreased inflammation was a significant inhibition of the development of allergen-induced in vivo AHR after STAT6 siRNA treatment, compared with GFP siRNA-treated sensitized and challenged controls. Importantly, mRNA and protein expression levels of IL-4 and IL-13 in lung tissues of STAT6-siRNA treated mice were significantly diminished compared with sensitized and challenged controls. These data show that targeting the key transcription factor STAT6 by siRNA effectively blocks the development of cardinal features of allergic airway disease, like allergen-induced airway inflammation and AHR. It may thus be considered as putative approach for treatment of allergic airway diseases such as asthma.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by a grant from the RiNA Network RNA-Technology Project 10, Grant 0313066D-10 from the Federal Ministry of Education and Research (BMBF), Grant 3066D-10 from the Senate of Berlin and Brandenburg (to E.H. and W.H.) and by Grant SFB650 from Deutsche Forschungsgemeinschaft (to A.K. and C.L.).

² Address correspondence and reprint requests to Dr. Eckard Hamelmann, University Children’s Hospital, Ruhr-University Bochum, Alexandrinenstrasse 5, 44791 Bochum, Germany. E-mail address: eckard.hamelmann{at}klinikum-bochum.de

³ Abbreviations used in this paper: siRNA, small interfering RNA; AHR, airway hyperreactivity; BAL, bronchoalveolar lavage; i.n., intranasal; siGFP, GFP-specific siRNA.