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 Citations (Scopus)

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

Fingerprint

Adenoviridae
Liver
Interleukin-10
Modulation
Galactosamine
Wounds and Injuries
Lipopolysaccharides
Gene therapy
Gene expression
Carrier Proteins
Anti-Inflammatory Agents
Intravenous Administration
Genetic Therapy
Hepatocytes
Gene Expression
Proteins

Keywords

  • Apoptosis
  • Cytokine
  • Gene therapy
  • Inflammation
  • Lipopolysaccharide

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Toxicology

Cite this

Oberholzer, C., Oberholzer, A., Tschoeke, S. K., Minter, R. M., Bahjat, F. R., LaFace, D., ... 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

Influence of recombinant adenovirus on liver injury in endotoxicosis and its modulation by IL-10 expression. / Oberholzer, Caroline; Oberholzer, Andreas; Tschoeke, Sven K.; Minter, Rebecca M.; Bahjat, Frances R.; LaFace, Drake; Hutchins, Beth; Moldawer, Lyle L.

In: Journal of Endotoxin Research, Vol. 10, No. 6, 22.12.2004, p. 393-401.

Research output: Contribution to journalArticle

Oberholzer, C, Oberholzer, A, Tschoeke, SK, Minter, RM, Bahjat, FR, LaFace, D, Hutchins, B & Moldawer, LL 2004, 'Influence of recombinant adenovirus on liver injury in endotoxicosis and its modulation by IL-10 expression', Journal of Endotoxin Research, vol. 10, no. 6, pp. 393-401. https://doi.org/10.1179/096805104225005832
Oberholzer, Caroline ; Oberholzer, Andreas ; Tschoeke, Sven K. ; Minter, Rebecca M. ; Bahjat, Frances R. ; LaFace, Drake ; Hutchins, Beth ; Moldawer, Lyle L. / Influence of recombinant adenovirus on liver injury in endotoxicosis and its modulation by IL-10 expression. In: Journal of Endotoxin Research. 2004 ; Vol. 10, No. 6. pp. 393-401.
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