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Anti–tumor necrosis factor α treatment promotes apoptosis and prevents liver regeneration in a transgenic mouse model of chronic hepatitis C
Author(s) -
Brenndörfer Erwin Daniel,
Weiland Malin,
Frelin Lars,
Derk Emma,
Ahlén Gustaf,
Jiao Jian,
Bode Johannes Georg,
Sällberg Matti
Publication year - 2010
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.23870
Subject(s) - tumor necrosis factor alpha , chemokine , apoptosis , immunology , inflammation , biology , medicine , biochemistry
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. (H EPATOLOGY 2010;.)