期刊
JOURNAL OF VIROLOGY
卷 76, 期 11, 页码 5515-5521出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.76.11.5515-5521.2002
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资金
- NCI NIH HHS [P30-CA13330, R01 CA72963, P30 CA013330] Funding Source: Medline
- NIAID NIH HHS [R01 AI42295, 2 T32 AI07506, T32 AI007506] Funding Source: Medline
Recombinant adenoviruses (Ads) are useful tools in gene transfer because they are able to infect a wide variety of tissues and cell types and do not require a replicating target cell. However, transgene expression is only transient due to host innate and acquired immune responses to the virus. Most recombinant Ads have deletions of early region 3 (E3) genes, allowing more space for insertion of the transgene. Although the E3 region is not necessary for infection, it has been observed that these nonessential genes have immunomodulatory properties. We demonstrate here that the E3 region of Ad inhibits the activation of NF-kappaB induced by tumor necrosis factor alpha (TNF-alpha) and interleukin-1. Ad E3 is able to prevent NF-kappaB from entering the nucleus, where it is normally active. Ad E3 also appears to function by preventing the activation of the kinase complex, IKK, which is responsible for phosphorylation of IkappaB that retains NF-kappaB in the cytoplasm in an inactive state. The prevention of NF-kappaB activation has been mapped to a complex of two of the seven E3 products, E3-10.4K and E3-14.5K (RIDalpha/beta). These and other studies indicate that, by using Ad vectors containing the E3 region, it may be possible to reduce the harmful proinflammatory effects of TNF-alpha and other cytokines that compromise the use of Ad gene therapy vectors in vivo.
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