Rescue of in vivo FAS-induced apoptosis of hepatocytes by corticosteroids either associated with alcohol consumption by mice or provided exogenously.
The pathogenic effects of many hepatic viral infections are mediated, at least in part, by the immune response to the infected hepatocyte. The immune response in the infected liver involves the interaction of cytotoxic T cells (CTL) with the hepatocytes through the interaction of FAS-ligand on the CTL and FAS on the hepatocyte. The initial hypothesis for this study was that alcohol consumption by mice would sensitize the liver to apoptosis induced by ligation of FAS. C57Bl/6 mice fed ethanol in a liquid diet did show an increased percentage of apoptotic cells 2 h after injection with anti-FAS as compared with the percentage in the control mice. However, 4 and 6 h after anti-FAS injection, control mice showed high percentages of apoptotic cells (20% to 41%) compared with 5% and 4% apoptotic cells in the ethanol-fed mice. The decreased apoptosis of ethanol-fed mice correlated closely with corticosterone levels in the sera. This was confirmed by the finding that adrenalectomized (ADX) mice provided a high level of corticosterone in drinking water were protected against FAS-induced hepatocyte apoptosis. Ethanol-fed mice showed a significant elevation of serum alanine aminotransferase (ALT) levels indicating the development of hepatitis in spite of the relatively low proportion of apoptotic cells in the liver. In conclusion, high levels of corticosterone protect hepatocytes from FAS-mediated apoptosis, but do not prevent the ultimate development of liver damage. In experiments where mice were provided ethanol chronically in drinking water, where stress is minimal, higher levels of ALT were noted in animals in the ethanol group as compared with animals in the control group. These data support the suggestion that ethanol increases hepatocyte sensitivity to FAS-mediated damage.
Sosa
Laura
L
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE 68105, USA.
Vidlak
Debbie
D
Strachota
Jennifer M
JM
Pavlik
Jackie
J
Jerrells
Thomas R
TR
D000305:Adrenal Cortex Hormones / Q000097:blood / Q000494:pharmacology*; D000315:Adrenalectomy; D000428:Alcohol Drinking / Q000378:metabolism*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D003586:Cytomegalovirus Infections / Q000378:metabolism; D000431:Ethanol / Q000494:pharmacology; D005260:Female; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015151:Immunoblotting; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D019014:fas Receptor / Q000096:biosynthesis* / Q000276:immunology
D000305:Adrenal Cortex Hormones; D000911:Antibodies, Monoclonal; D019014:fas Receptor; D000431:Ethanol