Anti-tumor necrosis factor α treatment promotes apoptosis and prevents liver regeneration in a transgenic mouse model of chronic hepatitis C.
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.
Brenndörfer
Erwin Daniel
ED
Division of Clinical Microbiology, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden.
Weiland
Malin
M
Frelin
Lars
L
Derk
Emma
E
Ahlén
Gustaf
G
Jiao
Jian
J
Bode
Johannes Georg
JG
Sällberg
Matti
M
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
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