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Growth differentiation factor-15: induction in liver injury through p53 and tumor necrosis factor-independent

Teresa A Zimmers1, Xiaoling Jin, Edward C Hsiao

  • 1DeWitt Daughtry Family Department of Surgery and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida 33136, USA.

The Journal of Surgical Research
|September 13, 2005
PubMed

Insights

Growth/differentiation factor-15 (GDF-15) is rapidly induced in liver injury, independent of protein synthesis. This immediate early response to liver damage involves pathways distinct from tumor necrosis factor (TNF) and p53 signaling.

Area of Science:

  • Molecular biology
  • Hepatology
  • Cellular stress response

Background:

  • Macrophage inhibitory cytokine-1 (MIC-1) and its murine ortholog, growth/differentiation factor-15 (GDF-15), are members of the transforming growth factor-beta superfamily.
  • Expression of GDF-15/MIC-1 is induced in hepatocytes following various forms of stress, including surgical/chemical injury and heat shock.

Purpose of the Study:

  • To investigate the evolutionary conservation of GDF-15/MIC-1 regulation in human liver disease.
  • To elucidate the molecular pathways regulating GDF-15 induction in response to liver injury.

Main Methods:

  • Analysis of MIC-1 expression in diseased human livers.
  • Assessment of Gdf15 induction in mouse models of liver injury.
  • Investigation of Gdf15 regulation in the absence of protein synthesis.
  • Examination of Gdf15 induction in mice deficient for TNF receptor subtypes and p53.

Main Results:

  • MIC-1 expression was induced in diseased human livers, suggesting conserved regulation.
  • Gdf15 induction by liver injury was independent of de novo protein synthesis, characteristic of immediate-early genes.
  • While tumor necrosis factor (TNF) could induce GDF-15, injury-induced Gdf15 expression was not dependent on TNF receptor signaling.
  • Liver injury-induced Gdf15 expression remained unchanged in p53-null mice, indicating p53-independent regulation.

Conclusions:

  • GDF-15 induction represents an evolutionarily conserved, immediate early response to liver injury.
  • The regulation of GDF-15 during liver injury involves signaling pathways independent of both TNF and p53.

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