期刊
MOLECULAR THERAPY
卷 12, 期 3, 页码 451-459出版社
CELL PRESS
DOI: 10.1016/j.ymthe.2005.04.008
关键词
innate immunity; plasmid DNA; enclothelial cell; macrophage
资金
- NCI NIH HHS [CA86224-01] Funding Source: Medline
Gene delivery by intravenous injection of cationic liposome-DNA complexes (LDC) can generate efficient transgene expression in the lungs and other organs, but the duration of expression is typically short. Previous studies have suggested a major role for interferon-gamma (IFN-gamma) and TNF in this process. However, plasmid DNA is also capable of eliciting production of type I IFNs. Therefore, we assessed the ability of LDC to elicit production of type I IFNs in vivo and assessed the effects of type I IFNs on suppression of transgene expression following in vivo gene delivery with LDC. Injection of LDC was found to induce production of high levels of both IFN-alpha and IFN-beta in vivo. Moreover, the levels of transgene expression following in vivo gene delivery were markedly increased in mice lacking functional type I IFN receptor genes, compared to wild-type mice or mice lacking IFN-gamma or TNF receptors. Addition of recombinant IFN-alpha and IFN-beta inhibited transgene expression by in vitrotransfected endothelial cells, and incubation of macrophages with LDC in vitro triggered production of both IFN-alpha and IFN-beta. Therefore, type I IFNs appear to play a key role in suppressing transgene expression in vivo following systemic nonviral gene delivery using LDC.
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