Influence of recombinant adenovirus on liver injury in endotoxicosis and its modulation by IL-10 expression

• Published in: Journal of endotoxin research 2004-01, Vol.10 (6), p.393-401
• Main Authors: Oberholzer, Caroline, Oberholzer, Andreas, Tschoeke, Sven K., Minter, Rebecca M., Bahjat, Frances R., LaFace, Drake, Hutchins, Beth, Moldawer, Lyle L.
• Format: Article
• Language: English
• Subjects: Adenovirus
• ISSN: 0968-0519; 1743-2839
• DOI: 10.1179/096805104225005832

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- alpha -dependent liver injury. The aim of this study was to evaluate whether the systemic administration of recombinant adenovirus exacerbates a subsequent TNF- alpha -dependent liver injury induced by D-galactosamine and lipopolysaccharide. Surprisingly, low-dose adenovirus administration (10 super(5) particles) protects, while high-dose adenovirus (10 super(10) particles) is associated with an exaggerated hepatic inflammatory response from a subsequent D-galactosamine and lipopolysaccharide challenge. This exacerbation is TNF- alpha 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- alpha appearance and attenuates the increased hepatocyte injury. Taken together, this report demonstrates potential additive effects of TNF- alpha 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.