Transforming growth factor-α attenuates hepatic fibrosis: possible involvement of matrix metalloproteinase-1

Liver Int. 2011 Apr;31(4):572-84. doi: 10.1111/j.1478-3231.2011.02475.x. Epub 2011 Feb 15.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cells, Cultured
  • Choline
  • DNA Primers / genetics
  • Diet*
  • Enzyme-Linked Immunosorbent Assay
  • Gene Expression Profiling
  • Hepatic Stellate Cells / metabolism*
  • Humans
  • Lipid Peroxidation / physiology
  • Liver / metabolism*
  • Liver Cirrhosis / metabolism*
  • Matrix Metalloproteinase 1 / metabolism*
  • Methionine / deficiency
  • Mice
  • Mice, Transgenic
  • Phosphorylation
  • Rats
  • Transforming Growth Factor alpha / genetics
  • Transforming Growth Factor alpha / metabolism*
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • DNA Primers
  • Transforming Growth Factor alpha
  • Methionine
  • p38 Mitogen-Activated Protein Kinases
  • Matrix Metalloproteinase 1
  • Choline