Type I interferons potently suppress gene expression following gene delivery using liposome(-)DNA complexes.
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 vitro-transfected 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.
Sellins
Karen
K
Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO 80523, USA.
Fradkin
Lee
L
Liggitt
Denny
D
Dow
Steven
S
D000818:Animals; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D005821:Genetic Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D066298:In Vitro Techniques; D007370:Interferon Type I / Q000378:metabolism*; D016898:Interferon-alpha / Q000096:biosynthesis; D016899:Interferon-beta / Q000096:biosynthesis / Q000378:metabolism; D008081:Liposomes / Q000737:chemistry / Q000378:metabolism*; D008156:Luciferases / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D010957:Plasmids / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D019076:Transgenes
D007370:Interferon Type I; D016898:Interferon-alpha; D008081:Liposomes; D016899:Interferon-beta; D004247:DNA; D008156:Luciferases