Abstract | BACKGROUND & AIMS: METHODS: We have used both genetic and pharmacologic approaches and analyzed liver injury, TLR4, cytokine and iNOS activation induced by BCG, BCG/LPS and D-GALN/LPS. RESULTS: BCG infection-induced liver injury is seen in wild-type mice but not in TNF(-/-), memTNF knock-in (KI), and sTNFR1-Fc transgenic mice. Severity of BCG-induced liver injury is correlated with BCG- granuloma number and hepatic expression of TLR4 and iNOS. In addition, protection from liver damage caused by BCG/LPS or D-GALN/LPS administration was observed in TNF(-/-), memTNF KI and sTNFR1-Fc transgenic mice. To extend the genetic findings, we then evaluated whether selective pharmacological inhibition of solTNF by dominant-negative (DN)-TNF neutralization and non-selective inhibition of solTNF and memTNF by anti-TNF antibodies and etanercept (TNFR2-IgG1) can protect the mice from liver injury. Both selective and non-selective inhibition of solTNF protected mice from BCG/LPS and D-GALN/LPS-induced liver damage. CONCLUSIONS: These data suggest that memTNF is not mediating liver injury and that selective inhibition of solTNF sparing memTNF may represent a new therapeutic strategy to treat immune-mediated inflammatory liver diseases.
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Authors | Maria L Olleros, Dominique Vesin, Agathe L Fotio, Marie-Laure Santiago-Raber, Sébastien Tauzin, David E Szymkowski, Irene Garcia |
Journal | Journal of hepatology
(J Hepatol)
Vol. 53
Issue 6
Pg. 1059-68
(Dec 2010)
ISSN: 1600-0641 [Electronic] Netherlands |
PMID | 20813418
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. |
Chemical References |
- Lipopolysaccharides
- Receptors, Tumor Necrosis Factor, Type I
- Tnfrsf1a protein, mouse
- Tumor Necrosis Factor-alpha
- lipopolysaccharide, Escherichia coli O111 B4
- Nitric Oxide Synthase Type II
- Nos2 protein, mouse
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Topics |
- Animals
- Chemical and Drug Induced Liver Injury
(etiology, pathology, physiopathology)
- Granuloma
(etiology, pathology)
- Lipopolysaccharides
(toxicity)
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Mice, Transgenic
- Models, Biological
- Mycobacterium bovis
(pathogenicity)
- Nitric Oxide Synthase Type II
- Receptors, Tumor Necrosis Factor, Type I
(genetics, physiology)
- Solubility
- Tumor Necrosis Factor-alpha
(antagonists & inhibitors, deficiency, genetics, physiology)
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