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

Tumor necrosis factor (TNF)α, 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‐α antibody is also effective. Male Wistar rats 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‐α 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‐ α 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‐α antibody did not affect expression of mRNA for interleukin (IL) 1α, IL‐6, transforming growth factor β1, or TNF‐α. However, MIP‐2 mRNA expression, which is regulated by TNF‐α, was decreased significantly by anti‐TNF‐α 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‐α 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‐α plays an important role in inflammation and necrosis in alcohol‐induced liver injury and that treatment with anti‐TNF‐α antibody may be therapeutically useful in this disease.