title: Anti-tumor necrosis factor α treatment promotes apoptosis and prevents liver regeneration in a transgenic mouse model of chronic hepatitis C.
abstract: 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.
  
  
  CONCLUSIONS
  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.affiliation: Division of Clinical Microbiology, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden.
authors.forename: Erwin Daniel
authors.initials: ED
authors.lastname: Brenndörfer
authors.forename: Malin
authors.initials: M
authors.lastname: Weiland
authors.forename: Lars
authors.initials: L
authors.lastname: Frelin
authors.forename: Emma
authors.initials: E
authors.lastname: Derk
authors.forename: Gustaf
authors.initials: G
authors.lastname: Ahlén
authors.forename: Jian
authors.initials: J
authors.lastname: Jiao
authors.forename: Johannes Georg
authors.initials: JG
authors.lastname: Bode
authors.forename: Matti
authors.initials: M
authors.lastname: Sällberg
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002352:Carrier Proteins / Q000276:immunology; D018932:Chemokine CCL2 / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D005838:Genotype; D019698:Hepatitis C, Chronic / Q000276:immunology* / Q000628:therapy; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008115:Liver Regeneration; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000097:blood / Q000276:immunology* / Q000627:therapeutic use / Q000633:toxicity; D017361:Viral Nonstructural Proteins; D014764:Viral Proteins / Q000276:immunology
chemical_list: D002352:Carrier Proteins; D018932:Chemokine CCL2; D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; C455041:NS4A cofactor peptide, Hepatitis C virus; D014409:Tumor Necrosis Factor-alpha; D017361:Viral Nonstructural Proteins; D014764:Viral Proteins