Tumor Necrosis Factor-a Promotes Cholestasis-Induced Liver Fibrosis in the Mouse through Tissue Inhibitor of

Tumor necrosis factor (TNF)-a, which is a mediator of hepatotoxicity, has been implicated in liver fibrosis. However, the roles of TNF-a on hepatic stellate cell (HSC) activation and liver fibrosis are complicated and remain controversial. To explore this issue, the role of TNF-a in cholestasis-induced liver fibrosis was examined by comparing between TNF-a2/2 mice and TNF-a+/+ mice after bile duct ligation (BDL). Serum TNF-a levels in mice were increased by common BDL combined with cystic duct ligation (CBDL+CDL). TNF-a deficiency reduced liver fibrosis without affecting liver injury, inflammatory cell infiltration, and liver regeneration after CBDL+CDL. Increased expression levels of collagen a1(I) mRNA, transforming growth factor (TGF)-b mRNA, and a-smooth muscle actin (aSMA) protein by CBDL+CDL in the livers of TNF-a2/2mice were comparable to those in TNF-a+/+ mice. Exogenous administration of TNF-a decreased collagen a1(I) mRNA expression in isolated rat HSCs. These results suggest that the reduced fibrosis in TNF-a2/2 mice is regulated in post-transcriptional level. Tissue inhibitor of metalloproteinase (TIMP)-1 plays a crucial role in the pathogenesis of liver fibrosis. TIMP-1 expression in HSCs in the liver was increased by CBDL+CDL, and the induction was lower in TNF-a2/2 mice than in TNF-a+/+ mice. Fibrosis in the lobe of TIMP-12/2 mice with partial BDL was also reduced. These findings indicate that TNF-a produced by cholestasis can promote liver fibrosis via TIMP-1 production from HSCs. Thus, targeting TNF-a and TIMP-1 may become a new therapeutic strategy fo