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Electric foot shock stress‐induced exacerbation of α‐galactosylceramide–triggered apoptosis in mouse liver
Author(s) -
Chida Yoichi,
Sudo Nobuyuki,
Sonoda Junko,
Sogawa Hiroshi,
Kubo Chiharu
Publication year - 2004
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.20158
Subject(s) - liver injury , endocrinology , tunel assay , hepatocyte , medicine , apoptosis , endogenous opioid , terminal deoxynucleotidyl transferase , hepatitis , (+) naloxone , endogeny , immunology , antagonist , receptor , biology , opioid , biochemistry , in vitro , immunohistochemistry
Recently, liver natural killer T (NKT) cells, which are specifically stimulated by α‐galactosylceramide (α‐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 α‐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 α‐GalCer–induced hepatitis. Pre‐exposure of 12 hours of foot shock stress before α‐GalCer administration significantly enhanced α‐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 α‐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 μ‐opioid receptor antagonist, which thus suggests that an elevation of endogenous GCs, but not β‐endorphin, as responsible for such stress‐induced aggravation in mouse hepatitis models. In conclusion, foot shock stress‐induced elevation of endogenous GCs exacerbates α‐GalCer–initiated hepatic apoptosis through the expansion of liver NKT cells and the up‐regulation of hepatocyte Fas antigen. (H EPATOLOGY 2004;39:1131–1140.)