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NF-κB promotes leaky expression of adenovirus genes in a replication-incompetent adenovirus vector
The replication-incompetent adenovirus (Ad) vector is one of the most promising vectors for gene therapy; however, systemic administration of Ad vectors results in severe hepatotoxicities, partly due to the leaky expression of Ad genes in the liver. Here we show that nuclear factor-kappa B (NF-κB) m...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728692/ https://www.ncbi.nlm.nih.gov/pubmed/26814140 http://dx.doi.org/10.1038/srep19922 |
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author | Machitani, M. Sakurai, F. Wakabayashi, K. Nakatani, K. Shimizu, K. Tachibana, M. Mizuguchi, H. |
author_facet | Machitani, M. Sakurai, F. Wakabayashi, K. Nakatani, K. Shimizu, K. Tachibana, M. Mizuguchi, H. |
author_sort | Machitani, M. |
collection | PubMed |
description | The replication-incompetent adenovirus (Ad) vector is one of the most promising vectors for gene therapy; however, systemic administration of Ad vectors results in severe hepatotoxicities, partly due to the leaky expression of Ad genes in the liver. Here we show that nuclear factor-kappa B (NF-κB) mediates the leaky expression of Ad genes from the Ad vector genome, and that the inhibition of NF-κB leads to the suppression of Ad gene expression and hepatotoxicities following transduction with Ad vectors. Activation of NF-κB by recombinant tumor necrosis factor (TNF)-α significantly enhanced the leaky expression of Ad genes. More than 50% suppression of the Ad gene expression was found by inhibitors of NF-κB signaling and siRNA-mediated knockdown of NF-κB. Similar results were found when cells were infected with wild-type Ad. Compared with a conventional Ad vector, an Ad vector expressing a dominant-negative IκBα (Adv-CADNIκBα), which is a negative regulator of NF-κB, mediated approximately 70% suppression of the leaky expression of Ad genes in the liver. Adv-CADNIκBα did not induce apparent hepatotoxicities. These results indicate that inhibition of NF-κB leads to suppression of Ad vector-mediated tissue damages via not only suppression of inflammatory responses but also reduction in the leaky expression of Ad genes. |
format | Online Article Text |
id | pubmed-4728692 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-47286922016-02-01 NF-κB promotes leaky expression of adenovirus genes in a replication-incompetent adenovirus vector Machitani, M. Sakurai, F. Wakabayashi, K. Nakatani, K. Shimizu, K. Tachibana, M. Mizuguchi, H. Sci Rep Article The replication-incompetent adenovirus (Ad) vector is one of the most promising vectors for gene therapy; however, systemic administration of Ad vectors results in severe hepatotoxicities, partly due to the leaky expression of Ad genes in the liver. Here we show that nuclear factor-kappa B (NF-κB) mediates the leaky expression of Ad genes from the Ad vector genome, and that the inhibition of NF-κB leads to the suppression of Ad gene expression and hepatotoxicities following transduction with Ad vectors. Activation of NF-κB by recombinant tumor necrosis factor (TNF)-α significantly enhanced the leaky expression of Ad genes. More than 50% suppression of the Ad gene expression was found by inhibitors of NF-κB signaling and siRNA-mediated knockdown of NF-κB. Similar results were found when cells were infected with wild-type Ad. Compared with a conventional Ad vector, an Ad vector expressing a dominant-negative IκBα (Adv-CADNIκBα), which is a negative regulator of NF-κB, mediated approximately 70% suppression of the leaky expression of Ad genes in the liver. Adv-CADNIκBα did not induce apparent hepatotoxicities. These results indicate that inhibition of NF-κB leads to suppression of Ad vector-mediated tissue damages via not only suppression of inflammatory responses but also reduction in the leaky expression of Ad genes. Nature Publishing Group 2016-01-27 /pmc/articles/PMC4728692/ /pubmed/26814140 http://dx.doi.org/10.1038/srep19922 Text en Copyright © 2016, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Machitani, M. Sakurai, F. Wakabayashi, K. Nakatani, K. Shimizu, K. Tachibana, M. Mizuguchi, H. NF-κB promotes leaky expression of adenovirus genes in a replication-incompetent adenovirus vector |
title | NF-κB promotes leaky expression of adenovirus genes in a replication-incompetent adenovirus vector |
title_full | NF-κB promotes leaky expression of adenovirus genes in a replication-incompetent adenovirus vector |
title_fullStr | NF-κB promotes leaky expression of adenovirus genes in a replication-incompetent adenovirus vector |
title_full_unstemmed | NF-κB promotes leaky expression of adenovirus genes in a replication-incompetent adenovirus vector |
title_short | NF-κB promotes leaky expression of adenovirus genes in a replication-incompetent adenovirus vector |
title_sort | nf-κb promotes leaky expression of adenovirus genes in a replication-incompetent adenovirus vector |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728692/ https://www.ncbi.nlm.nih.gov/pubmed/26814140 http://dx.doi.org/10.1038/srep19922 |
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