Anti-tumor necrosis factor α treatment promotes apoptosis and prevents liver regeneration in a transgenic mouse model of chronic hepatitis C

Hepatology. 2010 Nov;52(5):1553-63. doi: 10.1002/hep.23870.


Tumor necrosis factor α (TNFα) has been implicated in a variety of inflammatory diseases, and anti-TNFα has been shown to improve therapy when added to standard of care in chronic hepatitis C virus (HCV) infection. In addition, patients with chronic HCV have increased serum levels of TNFα and the macrophage-attracting chemokine (C-C motif) ligand 2 (CCL2). A mouse model of chronic HCV with hepatic nonstructural (NS) 3/4A protein expression mimics the human infection through a reduced response to double-stranded RNA and cleavage of the T cell protein tyrosine phosphatase. The mice also display a resistance to TNFα in vivo. We therefore analyzed the relationship between NS3/4A and TNFα. Wild-type and NS3/4A-transgenic (Tg) mice were treated with TNFα/D-galactosamine (D-galN), acting through the TNF receptor 1 on hepatocytes and macrophages, or lipopolysaccharide (LPS)/D-galN, acting through Toll-like receptor 4 on sinusoidal endothelial cells, macrophages, and dendritic cells. Mice were analyzed for hepatic signaling, liver damage, TNFα, and CCL2. Similar to HCV-infected humans, NS3/4A-Tg mice displayed elevated basal levels of TNFα and CCL2. Treatment of NS3/4A-Tg mice with TNFα/D-galN or LPS/D-galN led to increased hepatic nuclear factor kappa B (NFκB) activation, increased TNFα and CCL2 levels, decreased apoptosis, and increased hepatocyte regeneration. Importantly, blocking NFκB activation (bortezomib) or administering anti-TNFα (infliximab) 4 hours after LPS/D-galN injection reversed the resistance of NS3/4A-Tg mice to TNFα-induced liver injury.

Conclusion: Resistance to TNFα seen in NS3/4A-Tg mice is explained by a hepatoprotective effect of NFκB and TNFα. Hence, anti-TNFα agents block these effects and are antiviral by promoting hepatocyte apoptosis and preventing hepatocyte regeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Carrier Proteins / immunology
  • Chemokine CCL2 / metabolism
  • Cytokines / blood
  • Genotype
  • Hepatitis C, Chronic / immunology*
  • Hepatitis C, Chronic / therapy
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Liver / metabolism
  • Liver / pathology
  • Liver Regeneration
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • NF-kappa B / physiology
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*
  • Tumor Necrosis Factor-alpha / blood
  • Tumor Necrosis Factor-alpha / immunology*
  • Tumor Necrosis Factor-alpha / therapeutic use
  • Tumor Necrosis Factor-alpha / toxicity
  • Viral Nonstructural Proteins
  • Viral Proteins / immunology


  • Carrier Proteins
  • Chemokine CCL2
  • Cytokines
  • Intracellular Signaling Peptides and Proteins
  • NF-kappa B
  • NS4A cofactor peptide, Hepatitis C virus
  • Tumor Necrosis Factor-alpha
  • Viral Nonstructural Proteins
  • Viral Proteins