Anti–tumor necrosis factor α treatment promotes apoptosis and prevents liver regeneration in a transgenic mouse model of chronic hepatitis C
✍ Scribed by Erwin Daniel Brenndörfer; Malin Weiland; Lars Frelin; Emma Derk; Gustaf Ahlén; Jian Jiao; Johannes Georg Bode; Matti Sällberg
- Publisher
- John Wiley and Sons
- Year
- 2010
- Tongue
- English
- Weight
- 654 KB
- Volume
- 52
- Category
- Article
- ISSN
- 0270-9139
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✦ Synopsis
Tumor necrosis factor a (TNFa) has been implicated in a variety of inflammatory diseases, and anti-TNFa 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 TNFa 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 doublestranded RNA and cleavage of the T cell protein tyrosine phosphatase. The mice also display a resistance to TNFa in vivo. We therefore analyzed the relationship between NS3/4A and TNFa. Wild-type and NS3/4A-transgenic (Tg) mice were treated with TNFa/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, TNFa, and CCL2. Similar to HCV-infected humans, NS3/4A-Tg mice displayed elevated basal levels of TNFa and CCL2. Treatment of NS3/4A-Tg mice with TNFa/D-galN or LPS/D-galN led to increased hepatic nuclear factor kappa B (NFjB) activation, increased TNFa and CCL2 levels, decreased apoptosis, and increased hepatocyte regeneration. Importantly, blocking NFjB activation (bortezomib) or administering anti-TNFa (infliximab) 4 hours after LPS/D-galN injection reversed the resistance of NS3/ 4A-Tg mice to TNFa-induced liver injury. Conclusion: Resistance to TNFa seen in NS3/ 4A-Tg mice is explained by a hepatoprotective effect of NFjB and TNFa. Hence, anti-TNFa agents block these effects and are antiviral by promoting hepatocyte apoptosis and preventing hepatocyte regeneration. (HEPATOLOGY 2010;52:1553-1563) H epatitis C virus (HCV) is a main cause of chronic hepatitis worldwide, with a significant proportion of infected patients developing liver fibrosis, liver cirrhosis, hepatocellular carcinoma, and/or liver failure. An estimated 170 million people are currently infected with HCV. The actual therapies based on interferon (IFN) and ribavirin can cure only approximately 55% of the treated patients depending on viral genotype. 1 The HCV genome consists of a 9.4-kb linear, single-stranded, positive-sense RNA molecule coding for 10 structural and nonstructural (NS) proteins (