Transforming growth factor-α attenuates hepatic fibrosis: possible involvement of matrix metalloproteinase-1
Article first published online: 15 FEB 2011
© 2011 John Wiley & Sons A/S
Volume 31, Issue 4, pages 572–584, April 2011
How to Cite
Ohyama, T., Yamazaki, Y., Sato, K., Horiguchi, N., Ichikawa, T., Kakizaki, S., Takagi, H. and Mori, M. (2011), Transforming growth factor-α attenuates hepatic fibrosis: possible involvement of matrix metalloproteinase-1. Liver International, 31: 572–584. doi: 10.1111/j.1478-3231.2011.02475.x
- Issue published online: 8 MAR 2011
- Article first published online: 15 FEB 2011
- Received 8 August 2010, Accepted 10 January 2011
- anti-fibrogenic gene;
- hepatic stellate cells;
- methionine- and choline-deficient diet;
Background: The effect of transforming growth factor (TGF)-α on fibrosis varies between cell types and the role of TGF-α in hepatic fibrosis has not been fully elucidated.
Methods: We examined the effect of TGF-α on hepatic fibrosis using TGF-α-expressing transgenic mice fed a methionine- and choline-deficient (MCD) diet and human hepatic stellate cells (HSCs) line LX-2, rat and human primary HSCs.
Results: Although the expression levels of the tissue inhibitor of metalloproteinases-1 and α1(I) collagen mRNA were unchanged, feeding the TGF-α transgenic mice the MCD diet resulted in greater expression of the murine functional analogue of matrix metalloproteinase-1 (MMP-1), MMP-13 mRNA and protein and attenuated hepatic fibrosis compared with wild-type mice. TGF-α overexpression did not affect the extent of the steatosis, oxidative stress and hepatic inflammation in the MCD diet-fed mice. The effect of TGF-α on the fibrogenic and anti-fibrogenic gene expressions varied between cell types in vitro. TGF-α increased MMP-1 mRNA expressions that were completely blocked by gefitinib in LX-2 cells. The extracellular signal-regulated kinase (ERK) 1/2, c-Jun N-terminal kinase and p38 pathways were involved in MMP-1 mRNA expression in LX-2 cells. Although TGF-α increased the phosphorylation of p38, the p38 inhibitor activated the RAS-ERK pathway and increased TGF-α-induced MMP-1 mRNA expression, which suggested that there may be a crosstalk between the RAS-ERK and the p38 pathways in LX-2 cells.
Conclusions: The TGF-α may attenuate hepatic fibrosis in part because of upregulation of the expression of MMP-1. The balance between fibrogenic and anti-fibrogenic gene expression and between the activity of the RAS-ERK and the p38 pathways may be crucial for the fibrotic process.