Chronic ethanol consumption inhibits hepatic natural killer cell activity and accelerates murine cytomegalovirus-induced hepatitis.
BACKGROUND
Chronic alcohol drinking accelerates the progression of liver disease in patients with hepatitis viral infection; however, the underlying mechanisms are not fully understood.


METHODS
Here, we examined the effects of chronic ethanol feeding on hepatic natural killer (NK) cells and liver injury in 2 murine models of liver injury: injection of synthetic double-stranded RNA polyinosinic-polycytidylic acid (poly I:C), which mimics viral infection, and infection with murine cytomegalovirus (MCMV). Mice were fed the Lieber-DeCarli liquid diet containing 5% (vol/vol) ethanol for 8 weeks, resulting in a significant decrease in the percentage and total number of NK cells in the liver.


RESULTS
In control, pair-fed mice, poly I:C injection induced NK cell accumulation in the liver and activated hepatic NK cell cytotoxicity, whereas such induction and activation were diminished in ethanol-fed mice. Treatment with poly I:C also induced expression of NKG2D, granzyme B, perforin, Fas L, TRAIL, and IFN-gamma on liver lymphocytes, which were delayed or reduced in ethanol-treated mice compared with pair-fed mice. In contrast, chronic ethanol feeding did not affect poly I:C-induced mild liver injury. Furthermore, MCMV infection activated hepatic NK cells and induced hepatic inflammation and injury. Chronic ethanol consumption inhibited hepatic NK cell activation during MCMV infection, but enhanced MCMV-induced liver injury, viral titer, and inflammation in the liver.


CONCLUSIONS
Taken together, these findings suggest that chronic ethanol consumption decreases hepatic NK activity, thereby accelerating MCMV-induced hepatitis and liver injury.
Pan
Hong-na
HN
Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20892, USA.
Sun
Rui
R
Jaruga
Barbara
B
Hong
Feng
F
Kim
Won-Ho
WH
Gao
Bin
B
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D001219:Aspartate Aminotransferases / Q000097:blood; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D003586:Cytomegalovirus Infections / Q000473:pathology*; D000431:Ethanol / Q000494:pharmacology*; D005434:Flow Cytometry; D006524:Hepatitis, Viral, Animal / Q000473:pathology*; D007694:Killer Cells, Natural / Q000187:drug effects*; D008099:Liver / Q000166:cytology* / Q000187:drug effects / Q000473:pathology; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011070:Poly I-C / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000998:Antiviral Agents; D002492:Central Nervous System Depressants; D000431:Ethanol; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D011070:Poly I-C