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Tumor necrosis factor-alpha inhibits peroxisome proliferator-activated receptor gamma activity at a posttranslational

Chin K Sung1, Hongyun She, Shigang Xiong

  • 1Dept. of Pathology, Keck School of Medicine of the Univ. of Southern California, 1333 San Pablo St., MMR 412, Los Angeles, CA 90089-9141, USA.

American Journal of Physiology. Gastrointestinal and Liver Physiology
|December 6, 2003
PubMed

Insights

Tumor necrosis factor-alpha (TNF-alpha) inhibits peroxisome proliferator-activated receptor gamma (PPARgamma) activity in liver cells. This occurs through reduced PPARgamma DNA binding and ERK1/2-mediated phosphorylation, not the NF-kappaB pathway.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Hepatology

Background:

  • Diminished peroxisome proliferator-activated receptor gamma (PPARgamma) activity is linked to hepatic stellate cell (HSC) activation, a key factor in liver fibrosis.
  • Understanding the regulation of PPARgamma by inflammatory mediators like tumor necrosis factor-alpha (TNF-alpha) is crucial for developing anti-fibrotic therapies.

Purpose of the Study:

  • To investigate how TNF-alpha regulates PPARgamma activity in cultured hepatic stellate cells (HSCs).
  • To elucidate the molecular mechanisms underlying TNF-alpha-mediated inhibition of PPARgamma transactivity.

Main Methods:

  • Quantitative analysis of PPARgamma mRNA and protein levels in HSCs treated with TNF-alpha.
  • Electrophoretic mobility shift assays (EMSA) to assess PPARgamma binding to its responsive element (PPRE).
  • Reporter gene assays to measure PPARgamma transactivation activity.
  • Western blotting to evaluate the activation of signaling pathways (ERK1/2, JNK, NF-kappaB) and PPARgamma phosphorylation.

Main Results:

  • TNF-alpha decreased PPARgamma mRNA levels but not protein expression in HSCs.
  • TNF-alpha reduced PPARgamma binding to the PPRE and its transactivation activity.
  • TNF-alpha increased ERK1/2 and JNK activation, leading to PPARgamma phosphorylation at Ser(82), which inhibits its activity.
  • The inhibitory effect of TNF-alpha on PPARgamma was independent of the NF-kappaB pathway.

Conclusions:

  • TNF-alpha inhibits PPARgamma transactivity in HSCs by reducing PPARgamma-DNA binding.
  • ERK1/2-mediated phosphorylation of PPARgamma at Ser(82) is a key mechanism for TNF-alpha-induced inhibition.
  • These findings highlight a novel regulatory pathway of PPARgamma in HSCs relevant to liver fibrosis.

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