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p38 alpha MAPK inhibits JNK activation and collaborates with IkappaB kinase 2 to prevent endotoxin-induced liver

Jan Heinrichsdorff1, Tom Luedde, Eusebio Perdiguero

  • 1Institute for Genetics, Centre for Molecular Medicine (CMMC), and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Zülpicher Str. 47, D-50674 Cologne, Germany.

EMBO Reports
|August 16, 2008
PubMed

Insights

p38alpha deficiency in liver cells enhances c-Jun amino-terminal kinase (JNK) activation but does not cause tumor necrosis factor (TNF)-induced liver damage alone. However, combined with IkappaB kinase 2 (IKK2) inhibition, it sensitizes the liver to damage.

Area of Science:

  • Hepatology
  • Immunology
  • Molecular Biology

Background:

  • Tumor necrosis factor (TNF)-induced cell death is linked to c-Jun amino-terminal kinase (JNK) activation.
  • The role of the p38 mitogen-activated protein kinase (MAPK) pathway in TNF-induced cell death was previously unclear.

Purpose of the Study:

  • To investigate the role of p38alpha in TNF-induced liver injury.
  • To determine the interplay between p38alpha, JNK, and nuclear factor-kappaB (NF-κB) signaling in liver protection.

Main Methods:

  • Hepatocyte-specific ablation of p38alpha in mice.
  • In vivo challenge with bacterial lipopolysaccharide (LPS).
  • Assessment of JNK activation and liver toxicity in genetically modified mice.

Main Results:

  • Hepatocyte-specific p38alpha deficiency led to excessive JNK activation in response to LPS.
  • p38alpha-deficient hepatocytes were resistant to LPS/TNF toxicity, indicating JNK activation alone is insufficient for liver damage.
  • Mice lacking both p38alpha and IkappaB kinase 2 (IKK2) in hepatocytes exhibited liver failure upon LPS injection.

Conclusions:

  • p38alpha plays a crucial role in preventing liver failure induced by LPS/TNF.
  • p38alpha collaborates with IKK2 to control JNK activation and protect the liver.
  • p38alpha deficiency sensitizes the liver to cytokine-induced damage when NF-κB signaling is partially inhibited.

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