NF-κB promotes leaky expression of adenovirus genes in a replication-incompetent adenovirus vector.
NF-κB promotes leaky expression of adenovirus genes in a replication-incompetent adenovirus vector.
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DOI：
10.1038/srep19922
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发表时间：
2016-01-27
影响因子：
4.6
通讯作者：
Mizuguchi H
中科院分区：
文献类型：
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作者：
Machitani M;Sakurai F;Wakabayashi K;Nakatani K;Shimizu K;Tachibana M;Mizuguchi H
无复制能力的腺病毒（Ad）载体是用于基因治疗的最有前途的载体之一;然而，全身施用Ad载体导致严重的肝毒性，部分原因是Ad基因在肝脏中的泄漏表达。我们发现核因子-κ B（NF-κB）介导Ad基因从Ad载体基因组中的泄漏表达，并且NF-κB的抑制导致Ad基因表达的抑制和Ad载体转导后的肝毒性。重组肿瘤坏死因子（TNF）-α激活NF-κB后，Ad基因的渗漏表达明显增强。NF-κB信号通路抑制剂和siRNA介导的NF-κB基因敲低可抑制Ad基因表达50%以上。当细胞被野生型Ad感染时，发现类似的结果。与常规Ad载体相比，表达显性负性IκBα（Adv-CADNIκBα）（其是NF-κB的负调节剂）的Ad载体介导了约70%的肝中Ad基因泄漏表达的抑制。Adv-CADNIκBα未诱导明显肝毒性。这些结果表明，NF-κB的抑制导致抑制Ad载体介导的组织损伤，不仅通过抑制炎症反应，而且通过减少Ad基因的泄漏表达。
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.