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In vivo transfection of a cis element ‘decoy’ against signal transducers and activators of transcription 6 (STAT6)-binding site ameliorates IgE-mediated late-phase reaction in an atopic dermatitis mouse model

Gene Therapy volume 11, pages 1753–1762 (2004)Cite this article

Abstract

Signal transducers and activators of transcription 6 (STAT6) play a crucial role in the transactivation of IL-4 and IL-13, which might be involved in the pathogenesis of atopic dermatitis (AD). We herein reported that the IgE-mediated late-phase reaction significantly decreased in STAT6-deficient (STAT6−/−) mice in AD model mice induced by intravenous injection of monoclonal anti-dinitrophenyl (DNP)-IgE antibody and subsequent skin testing with dinitrofluorobenzene. We therefore hypothesized that synthetic double-stranded DNA with a high affinity for STAT6 could be introduced in vivo as decoy cis elements to bind the transcriptional factor and block the gene activation contributing to the onset and progression of AD, thus providing effective therapy for AD. Treatment by the transfection of STAT6 decoy oligodeoxynucleotides (ODNs), but not scramble decoy ODN after sensitization by anti-DNP-IgE antibody, had a significant inhibitory effect on not only STAT6 binding to nuclei but also on the late-phase response. A histological analysis revealed that both edema and the infiltration of neutrophils and eosinophils significantly decreased in STAT6 decoy ODN-transfected mice. To examine the mechanism of the in vivo effect of STAT6 decoy ODN, we employed an in vitro mast cells culture system. After IgE receptor engagement, mast cells transfected by STAT6 decoy ODN exhibited normal histamine release, but their cytokine release (TNF-α, IL-6) markedly decreased. We herein report the first successful in vivo transfer of STAT6 decoy ODN to reduce the late-phase reaction, thereby providing a new therapeutic strategy for AD.

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Acknowledgements

We thank Ms Motoko Sekiya for her excellent technical assistance. This work was partially supported by the Cosmetology Research Foundation and grants (15790569 and 13670869) from the Ministry of Education, Japan.

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Authors and Affiliations

  1. Department of Dermatology and Immunodermatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan

    H Yokozeki, M-H Wu, K Sumi, S Awad, T Satoh & K Nishioka

  2. Department of Dermatology, School of Medicine, Nagasaki University, Nagasaki, Japan

    I Katayama

  3. Department of Host Defense, Research Institute for Microbial Disease, Osaka University, Suita, Osaka, Japan

    K Takeda & S Akira

  4. Division of Gene Therapy Science, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan

    Y Kaneda

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  1. H Yokozeki
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Yokozeki, H., Wu, MH., Sumi, K. et al. In vivo transfection of a cis element ‘decoy’ against signal transducers and activators of transcription 6 (STAT6)-binding site ameliorates IgE-mediated late-phase reaction in an atopic dermatitis mouse model. Gene Ther 11, 1753–1762 (2004). https://doi.org/10.1038/sj.gt.3302341

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