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Activation of NF-kB mediates ICAM-1 induction in respiratory cells exposed to an adenovirus-derived vector

Gene Therapy volume 8, pages 1436–1442 (2001)Cite this article

Abstract

Gene transfer to the respiratory tract by replication-deficient adenoviruses is limited by the induction of inflammatory and immune responses. We previously demonstrated that a E1-E3-deleted recombinant adenovirus carrying the expression cassette for the cystic fibrosis gene (Ad.CFTR) upregulates the expression of the pro-inflammatory intercellular adhesion molecule-1 (ICAM-1) both in vitro and in vivo. In the present work we suggest a role for the nuclear factor-kB (NF-kB) in Ad.CFTR-dependent up-regulation of ICAM-1 in respiratory epithelial A549 cells. Specifically, Ad.CFTR induced translocation of NF-kB into the nucleus and binding to the proximal −228/−218 NF-kB consensus sequence on the ICAM-1 promoter. Ad.CFTR also stimulated a 13-fold increase in NF-kB-dependent expression of the CAT reporter gene under the control of a region of the ICAM-1 promoter, including the proximal NF-kB consensus sequence. The Ad.CFTR-dependent increase of ICAM-1 mRNA was abolished by inhibitors of NF-kB, such as N-acetyl-L-cysteine, pyrrolidine dithiocarbamate, parthenolide and the synthetic peptide SN50. All these inhibitors abolished both Ad.CFTR-induced NF-kB DNA binding and transactivating activities. These results indicate a critical role of NF-kB in the pro-inflammatory response elicited by replication-deficient adenoviral vectors in respiratory cells. Gene Therapy (2001) 8, 1436–1442.

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Acknowledgements

We are grateful to Drs Monika Lusky and Majid Mehtali for helpful discussions, Dr Patrick S Moore for revising the manuscript, Ms Federica Quiri, Angela Bozzoli and Mr Paolo Faggionato for excellent technical assistance. The financial support of the ‘Fondo Riservato Centro Fibrosi Cistica’ from the ‘Azienda Ospedaliera di Verona’ is gratefully acknowledged.

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Authors and Affiliations

  1. Laboratory of Molecular Pathology, Cystic Fibrosis Center, Verona, Italy

    P Melotti, E Nicolis, A Tamanini, R Rolfini & G Cabrini

  2. Transgène, Strasbourg, France

    A Pavirani

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Melotti, P., Nicolis, E., Tamanini, A. et al. Activation of NF-kB mediates ICAM-1 induction in respiratory cells exposed to an adenovirus-derived vector. Gene Ther 8, 1436–1442 (2001). https://doi.org/10.1038/sj.gt.3301533

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