Essential role of tumor necrosis factor alpha in alcohol-induced liver injury in mice.
OBJECTIVE
Tumor necrosis factor (TNF)-alpha is associated with increased mortality in alcoholics, but its role in early alcohol-induced liver injury is not fully understood. Recently, it was shown that injury induced by the enteral alcohol delivery model of Tsukamoto and French was reduced by antibodies to TNF-alpha. To obtain clear evidence for or against the hypothesis that TNF-alpha is involved, we studied TNF receptor 1 (TNF-R1, p55) or 2 (TNF-R2, p75) knockout mice.


METHODS
Long-term enteral alcohol delivery was modified for male gene-targeted mice lacking TNF-R1 and TNF-R2. Animals were given a high-fat liquid diet continuously with either ethanol or isocaloric maltose-dextrin as a control for 4 weeks.


RESULTS
Ethanol elevated serum levels of alanine aminotransferase nearly 3-fold in wild-type and TNF-R2 knockout mice but not in TNF-R1 knockout mice. Likewise, ethanol caused severe liver injury in wild-type mice (pathology score, 5.5 +/- 0.6) and TNF-R2 knockout mice (pathology score, 5.0 +/- 0.4), but not in TNF-R1 knockout mice (pathology score, 0.8 +/- 0.4; P < 0.001).


CONCLUSIONS
Long-term ethanol feeding caused liver injury in wild-type and TNF-R2 knockout mice but not in TNF-R1 knockout mice, providing solid evidence in support of the hypothesis that TNF-alpha plays an important role in the development of early alcohol-induced liver injury via the TNF-R1 pathway. Moreover, the long-term enteral ethanol feeding technique we described for the first time for knockout mice provides a useful new tool for alcohol research.
Yin
M
M
Laboratory of Hepatobiology, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Wheeler
M D
MD
Kono
H
H
Bradford
B U
BU
Gallucci
R M
RM
Luster
M I
MI
Thurman
R G
RG
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001835:Body Weight; D002465:Cell Movement; D016207:Cytokines / Q000235:genetics; D000431:Ethanol / Q000652:urine; D005234:Fatty Liver / Q000209:etiology / Q000473:pathology; D007091:Image Processing, Computer-Assisted; D007962:Leukocytes / Q000473:pathology / Q000502:physiology; D008099:Liver / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000150:complications / Q000473:pathology / Q000503:physiopathology* / Q000652:urine; D008297:Male; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D009929:Organ Size; D020033:Protein Isoforms / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000502:physiology*
D016207:Cytokines; D020033:Protein Isoforms; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol; D000410:Alanine Transaminase