Tumor Necrosis Factor-α Promotes Cholestasis-Induced Liver Fibrosis in the Mouse through Tissue Inhibitor of Metalloproteinase-1 Production in Hepatic Stellate Cells

Tumor necrosis factor (TNF)-alpha, which is a mediator of hepatotoxicity, has been implicated in liver fibrosis. However, the roles of TNF-alpha on hepatic stellate cell (HSC) activation and liver fibrosis are complicated and remain controversial. To explore this issue, the role of TNF-alpha in cholestasis-induced liver fibrosis was examined by comparing between TNF-alpha(-/-) mice and TNF-alpha(+/)+mice after bile duct ligation (BDL). Serum TNF-alpha levels in mice were increased by common BDL combined with cystic duct ligation (CBDL+CDL). TNF-alpha 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)-beta mRNA, and alpha-smooth muscle actin (alpha SMA) protein by CBDL+CDL in the livers of TNF-alpha(-/-) mice were comparable to those in TNF-alpha(+/)+mice. Exogenous administration of TNF-a decreased collagen alpha 1(I) mRNA expression in isolated rat HSCs. These results suggest that the reduced fibrosis in TNF-alpha(-/-) 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-alpha(-/-) mice than in TNF-alpha(+/)+mice. Fibrosis in the lobe of TIMP-1(-/-) mice with partial BDL was also reduced. These findings indicate that TNF-alpha produced by cholestasis can promote liver fibrosis via TIMP-1 production from HSCs. Thus, targeting TNF-alpha and TIMP-1 may become a new therapeutic strategy for treating liver fibrosis in cholestatic liver injury.