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

Abstract

UNLABELLED:

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.

• Authors: Erwin Daniel Brenndörfer, Malin Weiland, Lars Frelin, Emma Derk, Gustaf Ahlén, Jian Jiao, Johannes Georg Bode, Matti Sällberg
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 52 Issue 5 Pg. 1553-63 (Nov 2010) ISSN: 1527-3350 [Electronic] United States
• PMID: 20886569 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

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