Essential role of tumor necrosis factor α in alcohol-induced liver injury in mice
M Yin, MD Wheeler, H Kono, BU Bradford, RM Gallucci… - Gastroenterology, 1999 - Elsevier
M Yin, MD Wheeler, H Kono, BU Bradford, RM Gallucci, MI Luster, RG Thurman
Gastroenterology, 1999•ElsevierBackground & Aims: Tumor necrosis factor (TNF)-α 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-α. To obtain clear evidence for or against the
hypothesis that TNF-α 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 …
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-α. To obtain clear evidence for or against the
hypothesis that TNF-α 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 …
Background & Aims
Tumor necrosis factor (TNF)-α 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-α. To obtain clear evidence for or against the hypothesis that TNF-α 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-α 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. GASTROENTEROLOGY 1999;117:942-952
Elsevier