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 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.
Iimuro
Y
Y
Department of Pharmacology, The University of North Carolina at Chapel Hill, 27599-7365, USA.
Gallucci
R M
RM
Luster
M I
MI
Kono
H
H
Thurman
R G
RG
D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D001219:Aspartate Aminotransferases / Q000097:blood; D015152:Blotting, Northern; D054426:Chemokine CXCL2; D002630:Chemotactic Factors / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D004041:Dietary Fats / Q000378:metabolism; D000431:Ethanol / Q000633:toxicity; D006520:Hepatitis, Animal / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008104:Liver Cirrhosis, Alcoholic / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D015846:Monokines / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology* / Q000378:metabolism
D000906:Antibodies; D054426:Chemokine CXCL2; D002630:Chemotactic Factors; D017931:DNA Primers; D004041:Dietary Fats; D007375:Interleukin-1; D015850:Interleukin-6; D015846:Monokines; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol; D001219:Aspartate Aminotransferases