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Inflammation regulates TMPRSS6 expression via STAT5

Delphine Meynard1, Chia Chi Sun1, Qifang Wu1

  • 1Program in Anemia Signaling Research, Division of Nephrology, Program in Membrane Biology, Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.

Plos One
|December 31, 2013
PubMed

Insights

Inflammation downregulates Transmembrane serine protease 6 (TMPRSS6) expression, impacting iron homeostasis. This occurs via decreased Stat5 phosphorylation, offering a new mechanism for inflammation-induced hepcidin regulation.

Area of Science:

  • Molecular biology
  • Immunology
  • Iron metabolism

Background:

  • Transmembrane serine protease 6 (TMPRSS6) regulates iron homeostasis by inhibiting hepcidin.
  • Hepcidin, a key regulator of iron, is upregulated by inflammation and influences immunity.
  • The effect of inflammation on TMPRSS6 expression and its regulatory mechanism remained unclear.

Purpose of the Study:

  • To investigate whether inflammation modulates TMPRSS6 expression.
  • To elucidate the underlying mechanism of inflammatory regulation of TMPRSS6.
  • To understand the role of TMPRSS6 in inflammation-induced hepcidin control.

Main Methods:

  • In vitro study using a human hepatoma cell line treated with interleukin-6.
  • In vivo study involving lipopolysaccharide injection in mice.
  • Analysis of TMPRSS6 expression and Stat5 phosphorylation.

Main Results:

  • Inflammation was found to downregulate TMPRSS6 expression both in vitro and in vivo.
  • The downregulation of TMPRSS6 by inflammation in mice was independent of the Bmp-Smad pathway.
  • Inflammation decreased Stat5 phosphorylation, and Stat5 was identified as a direct positive regulator of TMPRSS6 expression via promoter binding.

Conclusions:

  • Inflammation downregulates TMPRSS6 expression through decreased Stat5 phosphorylation.
  • Stat5 directly binds to the TMPRSS6 promoter, positively regulating its expression.
  • This inflammatory modulation of TMPRSS6, via Stat5, provides an additional mechanism for inflammation-driven hepcidin upregulation, affecting iron homeostasis and immunity.

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