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The glucocorticoid receptor gene as a candidate for gene therapy in asthma

Gene Therapy volume 6, pages 245–252 (1999)Cite this article

Abstract

Glucocorticoids (GC) are commonly used as anti-inflammatory drugs in asthma, but can produce serious secondary effects and, moreover, be inefficient in corticoresistant asthmatics. After binding to the glucocorticoid receptor (GR), they repress the synthesis of proinflammatory cytokines via inhibition of the transcription factors AP-1 and NF-κB. Since qualitative and quantitative defects of the GR have been reported in corticoresistant patients, the transfer of the GR gene in the lung epithelium, the primary site of inflammation in asthma, may restore sensitivity to GC in these patients. As a prerequisite to in vivo studies, we have transfected A549 human lung epithelial cells with a GR expression vector. Using AP-1 and NF-κB-dependent reporter gene assays and an immunoassay for the proinflammatory cytokine RANTES, we show that the overexpressed GR significantly repressed AP-1 and NF-κB activities in the absence of hormone and that the GC dexamethasone produced an additive inhibitory effect. The GC-independent repression of AP-1 and NF-κB activities was further demonstrated by overexpressing a ligand- binding deficient GR mutant. Our data suggest that delivery of the GR gene in vivo may reduce inflammation without recourse to GC and may constitute an alternative therapeutic approach for corticoresistant asthma.

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Authors and Affiliations

  1. Institut National de la Santé et de la Recherche Médicale, U454 and the Service des Maladies Respiratoires, CHU de Montpellier, Montpellier, France

    M Mathieu, C Gougat, D Jaffuel, P Godard, J Bousquet & P Demoly

  2. Department of Biochemistry and Molecular Biology, Georgetown University Medical School, Washington, DC, USA

    M Danielsen

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  1. M Mathieu
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  2. C Gougat
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Mathieu, M., Gougat, C., Jaffuel, D. et al. The glucocorticoid receptor gene as a candidate for gene therapy in asthma. Gene Ther 6, 245–252 (1999). https://doi.org/10.1038/sj.gt.3300814

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