TNFα is required for cholestasis-induced liver fibrosis in the mouse

TNF alpha, a mediator of hepatotoxicity in several animal models, is elevated in acute and chronic liver diseases. Therefore, we investigated whether hepatic injury and fibrosis due to bile duct ligation (BDL) would be reduced in TNF alpha knockout mice (TNF alpha-/-). Survival after BDL was 60% in wild-type mice (TNF alpha+/+) and 90% in TNF alpha-/- mice. Body weight loss and liver to body weight ratios were reduced in TNFa-/- mice compared to TNF alpha+/+ mice. Following BDL, serum alanine transaminases (ALT) levels were elevated in TNF alpha+/+ mice (268.6 +/- 28.2 U/L) compared to TNF alpha-/- mice (105.9 U/L +/- 24.4). TNF alpha-/- mice revealed lower hepatic collagen expression and less liver fibrosis in the histology. Further, alpha-smooth muscle actin, an indicator for activated myofibroblasts, and TGF-beta mRNA, a profibrogenic cytokine, were markedly reduced in TNF alpha-/- mice compared to TNF alpha+/+ mice. Thus, our data indicate that TNF alpha induces hepatotoxicity and promotes fibrogenesis in the BDL model. (C) 2008 Elsevier Inc. All rights reserved.