| First Author | Osawa Y | Year | 2013 |
| Journal | PLoS One | Volume | 8 |
| Issue | 6 | Pages | e65251 |
| PubMed ID | 23755201 | Mgi Jnum | J:204251 |
| Mgi Id | MGI:5529888 | Doi | 10.1371/journal.pone.0065251 |
| Citation | Osawa Y, et al. (2013) Tumor necrosis factor-alpha promotes cholestasis-induced liver fibrosis in the mouse through tissue inhibitor of metalloproteinase-1 production in hepatic stellate cells. PLoS One 8(6):e65251 |
| abstractText | 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 alpha1(I) mRNA, transforming growth factor (TGF)-beta mRNA, and alpha-smooth muscle actin (alphaSMA) protein by CBDL+CDL in the livers of TNF-alpha(-/-) mice were comparable to those in TNF-alpha(+/+) mice. Exogenous administration of TNF-alpha decreased collagen alpha1(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. |
