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

Abstract

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.

Transcriptome analysis identifies TNF superfamily receptors as potential therapeutic targets in alcoholic hepatitis

“…The results of this study could be relevant, since it could provide useful human data to research groups devoted to the study of ALD. Importantly, some of the results obtained in our study differ from those obtained in rodents exposed to alcohol (ie, the lack of hepatic upregulation of TNFα and its specific receptors) 4 5. These discrepancies between human and experimental data reinforce the need to develop an experimental model that reproduces all the features of AH.…”

“…The most relevant agonists include TNFα, TNF-like weak inducer of apoptosis (TWEAK) and Fas ligand. Studies from experimental models of alcoholic liver injury have implicated TNFα, Fas ligand and their receptors in liver damage and remodelling 4 5 19 20. Little is known on the role of TWEAK and its specific receptor Fn14.…”

Fish oil improves lipid metabolism and ameliorates inflammation in patients with metabolic syndrome: Impact of nonalcoholic fatty liver disease

“…We found that patients with both MetS and NAFLD showed a significant increase in serum level of both TNF-α and IL-6. TNF-α level correlates well with liver disease severity, as demonstrated by reported studies (Iimuro et al, 1997). Much evidence supports the pathophysiological role of TNF-α in NAFLD, such as higher TNF-α mRNA expression in nonalcoholic steatohepatitis (NASH) patients with hepatic fibrosis, and increased prevalence of TNF-α polymorphisms in NAFLD patients (Copaci et al, 2006).…”

New Insights into the Regulation of Liver Inflammation and Oxidative Stress

“…Although this cytokine exerts pleiotropic effects in the context of the liver, its major effects are associated with the regulation of hepatocyte proliferation and apoptosis and the induction of inflammatory response [82,83]. The biological effects of TNF-are mediated by its interaction with two plasma membrane receptors: TNF-R1 and TNF-R2.…”