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NF-κB promotes leaky expression of adenovirus genes in a replication-incompetent adenovirus vector.
- Source :
-
Scientific reports [Sci Rep] 2016 Jan 27; Vol. 6, pp. 19922. Date of Electronic Publication: 2016 Jan 27. - Publication Year :
- 2016
-
Abstract
- 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.
- Subjects :
- Adenovirus E2 Proteins genetics
Animals
Binding Sites
Cell Line
Female
Humans
Interferon-alpha pharmacology
Liver metabolism
Liver virology
Mice
Mice, Knockout
Promoter Regions, Genetic
Protein Binding
Sequence Deletion
Transcriptional Activation
Virus Replication drug effects
Adenoviridae genetics
Gene Expression Regulation, Viral drug effects
Genetic Vectors genetics
NF-kappa B metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2045-2322
- Volume :
- 6
- Database :
- MEDLINE
- Journal :
- Scientific reports
- Publication Type :
- Academic Journal
- Accession number :
- 26814140
- Full Text :
- https://doi.org/10.1038/srep19922