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

Yosuke Osawa, Masato Hoshi, Ichiro Yasuda, Toshiji Saibara, Hisataka Moriwaki, Osamu Kozawa

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33 Citations (Scopus)


Tumor necrosis factor (TNF)-α, which is a mediator of hepatotoxicity, has been implicated in liver fibrosis. However, the roles of TNF-α on hepatic stellate cell (HSC) activation and liver fibrosis are complicated and remain controversial. To explore this issue, the role of TNF-α in cholestasis-induced liver fibrosis was examined by comparing between TNF-α-/- mice and TNF-α+/+ mice after bile duct ligation (BDL). Serum TNF-α levels in mice were increased by common BDL combined with cystic duct ligation (CBDL+CDL). TNF-α deficiency reduced liver fibrosis without affecting liver injury, inflammatory cell infiltration, and liver regeneration after CBDL+CDL. Increased expression levels of collagen α1(I) mRNA, transforming growth factor (TGF)-β mRNA, and α-smooth muscle actin (αSMA) protein by CBDL+CDL in the livers of TNF-α-/- mice were comparable to those in TNF-α+/+ mice. Exogenous administration of TNF-α decreased collagen α1(I) mRNA expression in isolated rat HSCs. These results suggest that the reduced fibrosis in TNF-α-/- 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-α-/- mice than in TNF-α+/+ mice. Fibrosis in the lobe of TIMP-1-/- mice with partial BDL was also reduced. These findings indicate that TNF-α produced by cholestasis can promote liver fibrosis via TIMP-1 production from HSCs. Thus, targeting TNF-α and TIMP-1 may become a new therapeutic strategy for treating liver fibrosis in cholestatic liver injury.

Original languageEnglish
Article numbere65251
JournalPloS one
Issue number6
Publication statusPublished - 03-06-2013
Externally publishedYes


All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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