Chronic hepatitis in interferon-gamma transgenic mice is associated with elevated CPP32-like activity and

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T Okamoto1, Y Nakano, T Yamakawa

  • 1Research Laboratories, Nippon Chemiphar Co., Ltd., Saitama, Japan.

Japanese Journal of Pharmacology
|May 7, 1999
PubMed

Insights

Interferon-gamma (IFN-gamma) transgenic mice develop chronic hepatitis. This study found reduced interleukin-1beta-converting enzyme (ICE) and increased CPP32-like protease activity in their livers, linking these protease changes to liver injury.

Area of Science:

  • Hepatology
  • Immunology
  • Molecular Biology

Background:

  • Interferon-gamma (IFN-gamma) transgenic mice exhibit liver expression of IFN-gamma, leading to chronic hepatitis.
  • Hepatocyte apoptosis is a key feature of liver damage in these mice.

Purpose of the Study:

  • To investigate the roles of interleukin-1beta-converting enzyme (ICE) and CPP32-like protease activity in the pathogenesis of chronic hepatitis in IFN-gamma transgenic mice.
  • To elucidate the specific protease activities contributing to liver injury.

Main Methods:

  • Measurement of ICE and CPP32-like protease activities in liver cytosol using synthetic substrates (Ac-YVAD-MCA and Ac-DEVD-MCA).
  • Assessment of plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities.
  • Inhibition studies using Ac-YVAD-CHO (ICE inhibitor) and a CPP32 inhibitor on liver cell cytosol.

Main Results:

  • Significantly elevated plasma AST and ALT activities, indicative of liver damage.
  • Significantly reduced ICE activity and significantly induced CPP32-like protease activity in the liver of IFN-gamma transgenic mice.
  • ICE inhibition did not affect CPP32 activity, whereas CPP32 inhibition did, suggesting distinct roles.

Conclusions:

  • Chronic hepatitis in IFN-gamma transgenic mice is characterized by a decrease in ICE activity.
  • The induction of CPP32-like protease activity is associated with liver injury in this model.
  • These findings highlight the differential involvement of caspases in IFN-gamma-mediated liver disease.

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