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

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 mts were exposed to ethanol (11 to 12 g.kg(-1).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 fourfold 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) 1 alpha, IL-6, transforming growth factor beta(1), 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.