title: Tumor necrosis factor-α promotes cholestasis-induced liver fibrosis in the mouse through tissue inhibitor of metalloproteinase-1 production in hepatic stellate cells.
abstract: 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.
authors.affiliation: Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu, Gifu, Japan. osawa-gif@umin.ac.jp
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Osawa
authors.forename: Masato
authors.initials: M
authors.lastname: Hoshi
authors.forename: Ichiro
authors.initials: I
authors.lastname: Yasuda
authors.forename: Toshiji
authors.initials: T
authors.lastname: Saibara
authors.forename: Hisataka
authors.initials: H
authors.lastname: Moriwaki
authors.forename: Osamu
authors.initials: O
authors.lastname: Kozawa
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002779:Cholestasis / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D003135:Common Bile Duct / Q000473:pathology; D003549:Cystic Duct / Q000473:pathology; D005786:Gene Expression Regulation; D055166:Hepatic Stellate Cells / Q000378:metabolism* / Q000473:pathology; D008103:Liver Cirrhosis / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051381:Rats; D017208:Rats, Wistar; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D000199:Actins; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; C560825:Timp1 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; C544013:alpha-smooth muscle actin, mouse