Abstract
Adenovirus-based gene therapy offers a unique opportunity to target gene expression to the liver by systemic delivery. However, systemic administration of a first generation adenoviral construct elicits an inflammatory response leading to TNF-α-dependent liver injury. The aim of this study was to evaluate whether the systemic administration of recombinant adenovirus exacerbates a subsequent TNF-α-dependent liver injury induced by D-galactosamine and lipopolysaccharide. Surprisingly, low-dose adenovirus administration (105 particles) protects, while high-dose adenovirus (1010 particles) is associated with an exaggerated hepatic inflammatory response from a subsequent D-galactosamine and lipopolysaccharide challenge. This exacerbation is TNF-α dependent, since treatment with a TNF inhibitor fully protects against the liver injury. Moreover, intravenous administration of an adenoviral construct expressing the anti-inflammatory protein interleukin-10 reduces TNF-α appearance and attenuates the increased hepatocyte injury. Taken together, this report demonstrates potential additive effects of TNF-α responses induced by adenovirus and other inflammatory signals, and suggests that the response can be mitigated by relative adenovirus particle dose or by inhibitors, such as TNF-binding protein or interleukin 10.
Original language | English (US) |
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Pages (from-to) | 393-401 |
Number of pages | 9 |
Journal | Journal of Endotoxin Research |
Volume | 10 |
Issue number | 6 |
DOIs | |
State | Published - 2004 |
Keywords
- Apoptosis
- Cytokine
- Gene therapy
- Inflammation
- Lipopolysaccharide
ASJC Scopus subject areas
- Microbiology
- Immunology
- Molecular Biology
- Cell Biology
- Infectious Diseases