1. ¹Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO 80523, USA
2. ²Valentis Corporation, Burlingame, CA, USA
3. ³Department of Comparative Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA
4. ⁴Department of Clinical Sciences, Colorado State University, Fort Collins, CO 80523, USA

Correspondence: Steven Dow, Fax: +1 970 491 0603. E-mail: sdow@colostate.edu

^*Current address: Laboratory of Developmental Neurobiology, Department of Molecular and Cell Biology, Sylvius Laboratory, Leiden University Medical Center, Wassenaarseweg 72, 2333 AL Leiden, The Netherlands.

Received 18 March 2005; Accepted 24 April 2005.

Abstract

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- (IFN-) 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- and IFN- 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- or TNF receptors. Addition of recombinant IFN- and IFN- inhibited transgene expression by in vitro-transfected endothelial cells, and incubation of macrophages with LDC in vitro triggered production of both IFN- and IFN-. Therefore, type I IFNs appear to play a key role in suppressing transgene expression in vivo following systemic nonviral gene delivery using LDC.