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Interferon alpha increases metalloproteinase-13 gene expression through a polyomavirus enhancer activator 3-dependent

Teresa Díaz-Sanjuán1, Inmaculada García-Ruiz, Cristina Rodríguez-Juan

  • 1Department of Gastroenterology, Research Center, Hospital Universitario 12 de Octubre, Avenida de Andalucia, s/n. Madrid, Spain.

Journal of Hepatology
|November 19, 2008
PubMed
Abstract

Insights

Interferon-alpha (IFNalpha) activates matrix metalloproteinase-13 (MMP-13) gene expression in hepatic stellate cells by promoting PEA3 binding to the MMP-13 promoter, involving JAK1 and STAT1 signaling pathways.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Hepatic stellate cells (HSCs) play a crucial role in liver fibrosis.
  • Matrix metalloproteinase-13 (MMP-13) is implicated in extracellular matrix remodeling.
  • Interferon-alpha (IFNalpha) is a cytokine with diverse biological functions.

Purpose of the Study:

  • To investigate the effect of IFNalpha on MMP-13 gene expression in primary HSCs.
  • To elucidate the molecular mechanisms underlying IFNalpha-mediated MMP-13 regulation.

Main Methods:

  • Measurement of MMP-13 mRNA and protein levels.
  • Luciferase reporter assays using MMP-13 promoter constructs.
  • Electrophoretic mobility shift assays (EMSAs) to assess transcription factor binding.
  • Co-immunoprecipitation and Western blot analyses to study protein interactions and phosphorylation.

Main Results:

  • IFNalpha significantly upregulated MMP-13 mRNA, protein, and promoter activity.
  • IFNalpha induced the binding of PEA3 transcription factor to the MMP-13 promoter.
  • PEA3 physically interacted with JAK1 and STAT1, and IFNalpha enhanced this interaction and PEA3 phosphorylation.
  • Downregulation of PEA3 or JAK1 abolished IFNalpha's effect on MMP-13 expression.

Conclusions:

  • IFNalpha activates MMP-13 gene expression in HSCs.
  • This activation is mediated by the recruitment of PEA3 to the MMP-13 promoter.
  • The JAK1-STAT1 signaling pathway is essential for IFNalpha-induced PEA3 activation and subsequent MMP-13 expression.

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