Anti-Tumor Necrosis Factor α Treatment Promotes Apoptosis and Prevents Liver Regeneration in a Transgenic Mouse Model of Chronic Hepatitis C

Tumor necrosis factor alpha (TNF alpha) has been implicated in a variety of inflammatory diseases, and anti-TNF alpha 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 TNF alpha 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 TNF alpha in vivo. We therefore analyzed the relationship between NS3/4A and TNF alpha. Wild-type and NS3/4A-transgenic (Tg) mice were treated with TNF alpha/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, TNF alpha, and CCL2. Similar to HCV-infected humans, NS3/4A-Tg mice displayed elevated basal levels of TNF alpha and CCL2. Treatment of NS3/4A-Tg mice with TNF alpha/D-galN or LPS/D-galN led to increased hepatic nuclear factor kappa B (NF kappa B) activation, increased TNF alpha and CCL2 levels, decreased apoptosis, and increased hepatocyte regeneration. Importantly, blocking NF kappa B activation (bortezomib) or administering anti-TNF alpha (infliximab) 4 hours after LPS/D-galN injection reversed the resistance of NS3/4A-Tg mice to TNF alpha-induced liver injury. Conclusion: Resistance to TNF alpha seen in NS3/4A-Tg mice is explained by a hepatoprotective effect of NF kappa B and TNF alpha. Hence, anti-TNF alpha agents block these effects and are antiviral by promoting hepatocyte apoptosis and preventing hepatocyte regeneration. (HEPATOLOGY 2010;52:1553-1563)