Antibodies to tumor necrosis factor alfa attenuate hepatic necrosis and inflammation caused by chronic exposure to ethanol in the rat

Hepatology. 1997 Dec;26(6):1530-7. doi: 10.1002/hep.510260621.


Tumor necrosis factor (TNF)alpha, a pivotal cytokine involved in inflammation, is produced primarily by Kupffer cells in the liver. It has been shown that inactivation of Kupffer cells prevents alcohol-induced liver injury; therefore, the purpose of this study was to determine if neutralizing anti-TNF-alpha antibody is also effective. Male Wistar rats were exposed to ethanol (11 to 12 g x kg(-1) x d[-1]) continuously for up to 4 weeks via intragastric feeding using an enteral feeding model. Before ethanol exposure, polyclonal anti-mouse TNF-alpha rabbit serum was injected (2.0 mg/kg intravenously). There were no significant differences in body weight, mean ethanol concentration, or cyclic patterns of ethanol in urine when ethanol- and ethanol plus antibody-treated groups were compared. Expression of TNF-alpha and macrophage inflammatory protein 2 (MIP-2) messenger RNA (mRNA), determined using reverse transcription-polymerase chain reaction, was three- to four-fold higher in livers of ethanol-treated rats than in those of rats fed an ethanol-free, high-fat control diet. In addition, MIP-2 levels were also elevated when detected by Northern blot analysis. Anti-TNF-alpha antibody did not affect expression of mRNA for interleukin (IL) 1alpha, IL-6, transforming growth factor beta1, or TNF-alpha. However, MIP-2 mRNA expression, which is regulated by TNF-alpha, was decreased significantly by anti-TNF-alpha antibody treatment. Serum aspartate transaminase levels were elevated in ethanol-treated rats to 136 +/- 12 IU/L after 4 weeks but only reached 90 +/- 5 IU/L (P < .05) in rats treated with anti-TNF-alpha antibody. The hepatic inflammation and necrosis observed in ethanol-fed rats were attenuated significantly by antibody treatment, and steatosis was not. These results support the hypothesis that TNF-alpha plays an important role in inflammation and necrosis in alcohol-induced liver injury and that treatment with anti-TNF-alpha antibody may be therapeutically useful in this disease.

Publication types

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

MeSH terms

  • Animals
  • Antibodies / pharmacology*
  • Aspartate Aminotransferases / blood
  • Blotting, Northern
  • Chemokine CXCL2
  • Chemotactic Factors / metabolism
  • DNA Primers / chemistry
  • Dietary Fats / metabolism
  • Ethanol / toxicity
  • Hepatitis, Animal / chemically induced
  • Hepatitis, Animal / metabolism
  • Hepatitis, Animal / pathology
  • Hepatitis, Animal / prevention & control*
  • Interleukin-1 / genetics
  • Interleukin-1 / metabolism
  • Interleukin-6 / genetics
  • Interleukin-6 / metabolism
  • Liver Cirrhosis, Alcoholic / etiology
  • Liver Cirrhosis, Alcoholic / metabolism
  • Liver Cirrhosis, Alcoholic / pathology
  • Liver Cirrhosis, Alcoholic / prevention & control*
  • Male
  • Monokines / genetics
  • Monokines / metabolism
  • RNA, Messenger / metabolism
  • Rabbits
  • Rats
  • Rats, Wistar
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism
  • Tumor Necrosis Factor-alpha / immunology*
  • Tumor Necrosis Factor-alpha / metabolism


  • Antibodies
  • Chemokine CXCL2
  • Chemotactic Factors
  • DNA Primers
  • Dietary Fats
  • Interleukin-1
  • Interleukin-6
  • Monokines
  • RNA, Messenger
  • Transforming Growth Factor beta
  • Tumor Necrosis Factor-alpha
  • Ethanol
  • Aspartate Aminotransferases