Differential role of p38 in IL-1alpha induction of MMP-9 and MMP-13 in an established liver myofibroblast cell line

J Biomed Sci. Nov-Dec 2003;10(6 Pt 2):757-65. doi: 10.1159/000073963.

Abstract

Interleukin-1 (IL-1) has been implicated in the regulation of the expression of various matrix metalloproteinases (MMPs) in many mesenchymal cell types, but its role in liver myofibroblasts (MFs) has not been elucidated. A myofibroblast-like cell line, MG2, was derived from an isolate of rat hepatic stellate cells (HSCs). These cells expressed desmin, vimentin, smooth muscle alpha-actin, and fibulin-2. Using a recombinant IL-1alpha at 5 ng/ml, it was shown that IL-1alpha would upregulate, while IL-1Ra, an IL-1 receptor antagonist, would down-regulate the expression of IL-1alpha mRNA in MG2 cells, indicating the presence of an autostimulatory loop of IL-1alpha in these cells. Besides, a paracrine source of IL-1 may be produced from Kupffer cells, as we showed primarily cultured Kupffer cells responded much more remarkably than MG2 cells to lipopolysaccharide stimuli to produce both IL-1alpha and IL-1beta. Recombinant IL-1alpha upregulated the expression of both MMP-9 and -13, and the induction of MMP-13 but not MMP-9 could be inhibited by SB203580, an inhibitor of p38. Similarly, in primarily cultured human liver MFs, upregulation of MMP-1 by IL-1alpha was also shown to be inhibited by SB203580. All of these data suggested that, during liver inflammation, IL-1 produced by an autocrine model from MFs or by a paracrine model from Kupffer cells might play a crucial role in the remodeling of liver fibrosis through an either p38-dependent or p38-independent pathway to regulate the expression of various MMPs by liver MFs.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Northern
  • Cell Count
  • Cell Line, Tumor
  • Collagenases / metabolism*
  • Down-Regulation / drug effects*
  • Enzyme-Linked Immunosorbent Assay
  • Histological Techniques
  • Humans
  • Imidazoles / metabolism
  • Interleukin-1 / pharmacology*
  • Kupffer Cells / drug effects
  • Lipopolysaccharides / metabolism
  • Liver Cirrhosis / physiopathology
  • Matrix Metalloproteinase 13
  • Matrix Metalloproteinase 9 / metabolism*
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / metabolism*
  • Pyridines / metabolism
  • Rats
  • Rats, Wistar
  • Reverse Transcriptase Polymerase Chain Reaction
  • Up-Regulation / drug effects*
  • p38 Mitogen-Activated Protein Kinases

Substances

  • Imidazoles
  • Interleukin-1
  • Lipopolysaccharides
  • Pyridines
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Collagenases
  • MMP13 protein, human
  • Matrix Metalloproteinase 13
  • Mmp13 protein, rat
  • Matrix Metalloproteinase 9
  • SB 203580