Electric foot shock stress-induced exacerbation of alpha-galactosylceramide-triggered apoptosis in mouse liver

Hepatology. 2004 Apr;39(4):1131-40. doi: 10.1002/hep.20158.


Recently, liver natural killer T (NKT) cells, which are specifically stimulated by alpha-galactosylceramide (alpha-GalCer), were found to play a critical role in intrahepatic immunity to several infections and certain hepatic disorders. However, the role of psychophysical stress on NKT cell-dependent liver injury induced by alpha-GalCer still remains to be elucidated. In this study, we employed inescapable electric foot shock as the mode of psychophysical stress and evaluated its effect on alpha-GalCer-induced hepatitis. Pre-exposure of 12 hours of foot shock stress before alpha-GalCer administration significantly enhanced alpha-GalCer-triggered increase in serum alanine aminotransferase levels, followed by increases in both liver caspase-3 activity and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive hepatocytes, thus indicating that the liver NKT cell-dependent apoptotic response was exacerbated by stress. Foot shock stress also significantly increased both the number of liver NKT cells and Fas expression levels on hepatocytes. Pretreatment with RU-486, a glucocorticoid (GC) receptor antagonist, completely reversed such stress-induced enhancement of the alpha-GalCer-triggered serum alanine aminotransferase and hepatocyte Fas antigen responses. In contrast, such a reversal effect was not found in the mice pretreated with naloxone, a micro-opioid receptor antagonist, which thus suggests that an elevation of endogenous GCs, but not beta-endorphin, as responsible for such stress-induced aggravation in mouse hepatitis models. In conclusion, foot shock stress-induced elevation of endogenous GCs exacerbates alpha-GalCer-initiated hepatic apoptosis through the expansion of liver NKT cells and the up-regulation of hepatocyte Fas antigen.

MeSH terms

  • Alanine Transaminase / blood
  • Animals
  • Apoptosis
  • Chemical and Drug Induced Liver Injury / immunology
  • Chemical and Drug Induced Liver Injury / metabolism*
  • Chemical and Drug Induced Liver Injury / pathology*
  • Electroshock
  • Galactosylceramides*
  • Liver / immunology
  • Liver / metabolism
  • Liver / pathology
  • Lymphocyte Subsets
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Receptors, Glucocorticoid / antagonists & inhibitors
  • Stress, Psychological / immunology
  • Stress, Psychological / metabolism*
  • Stress, Psychological / pathology*
  • Up-Regulation
  • fas Receptor / metabolism


  • Galactosylceramides
  • Receptors, Glucocorticoid
  • fas Receptor
  • Alanine Transaminase