Essential role of tumor necrosis factor alpha in alcohol-induced liver injury in mice

Gastroenterology. 1999 Oct;117(4):942-52. doi: 10.1016/s0016-5085(99)70354-9.


Background & aims: 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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alanine Transaminase / blood
  • Animals
  • Body Weight
  • Cell Movement
  • Cytokines / genetics
  • Ethanol / urine
  • Fatty Liver / etiology
  • Fatty Liver / pathology
  • Image Processing, Computer-Assisted
  • Leukocytes / pathology
  • Leukocytes / physiology
  • Liver / pathology
  • Liver Diseases, Alcoholic / complications
  • Liver Diseases, Alcoholic / pathology
  • Liver Diseases, Alcoholic / physiopathology*
  • Liver Diseases, Alcoholic / urine
  • Male
  • Mice
  • Mice, Knockout / genetics
  • Organ Size
  • Protein Isoforms / genetics
  • RNA, Messenger / metabolism
  • Receptors, Tumor Necrosis Factor / genetics
  • Tumor Necrosis Factor-alpha / metabolism
  • Tumor Necrosis Factor-alpha / physiology*


  • Cytokines
  • Protein Isoforms
  • RNA, Messenger
  • Receptors, Tumor Necrosis Factor
  • Tumor Necrosis Factor-alpha
  • Ethanol
  • Alanine Transaminase