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Induction of hepatitis by JNK-mediated expression of TNF-alpha

Madhumita Das1, Guadalupe Sabio, Feng Jiang

  • 1Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.

Cell
|January 27, 2009
PubMed

Insights

The c-Jun NH2-terminal kinase (JNK) pathway is crucial for tumor necrosis factor (TNF)-alpha expression in hematopoietic cells, not for hepatocyte death, during hepatitis development.

Area of Science:

  • Immunology
  • Hepatology
  • Molecular Biology

Background:

  • The c-Jun NH2-terminal kinase (JNK) signaling pathway is involved in tumor necrosis factor (TNF)-dependent hepatitis.
  • JNK's role in TNF-stimulated hepatocyte death in vivo requires further investigation.

Purpose of the Study:

  • To investigate the role of JNK1 and JNK2 in the development of TNF-dependent hepatitis.
  • To determine whether JNK is essential in hepatocytes or hematopoietic cells for hepatitis progression.

Main Methods:

  • Generation of mice with compound disruption of Jnk1 and Jnk2 genes.
  • Analysis of hepatitis phenotype in mice with hepatocyte-specific or hematopoietic-specific JNK1/2 deficiency.
  • Assessment of TNF-alpha expression and hepatic damage.

Main Results:

  • Mice lacking JNK1/2 in hepatocytes showed no defect in hepatitis development.
  • Mice lacking JNK1/2 in hematopoietic cells exhibited a significant defect in hepatitis.
  • Hepatitis in JNK-deficient mice was associated with reduced TNF-alpha expression.
  • TNF-alpha induced similar hepatic damage in both hepatocyte-specific JNK1/2-deficient and control mice.

Conclusions:

  • JNK is essential for TNF-alpha expression, but not for TNF-alpha-induced hepatocyte death.
  • Hematopoietic cells, not hepatocytes, are the critical site for JNK function in hepatitis development.

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