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

Caroline Oberholzer, Andreas Oberholzer, Sven K. Tschoeke, Rebecca M. Minter, Frances R. Bahjat, Drake LaFace, Beth Hutchins, Lyle L. Moldawer

Research output: Contribution to journalArticle

9 Scopus citations

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 languageEnglish (US)
Pages (from-to)393-401
Number of pages9
JournalJournal of Endotoxin Research
Volume10
Issue number6
DOIs
StatePublished - Dec 22 2004

Keywords

  • Apoptosis
  • Cytokine
  • Gene therapy
  • Inflammation
  • Lipopolysaccharide

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Molecular Biology
  • Cell Biology
  • Infectious Diseases

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  • Cite this

    Oberholzer, C., Oberholzer, A., Tschoeke, S. K., Minter, R. M., Bahjat, F. R., LaFace, D., Hutchins, B., & Moldawer, L. L. (2004). Influence of recombinant adenovirus on liver injury in endotoxicosis and its modulation by IL-10 expression. Journal of Endotoxin Research, 10(6), 393-401. https://doi.org/10.1179/096805104225005832