Role of tumor necrosis factor-alpha in the development of spontaneous hepatic toxicity in Long-Evans Cinnamon rats

The objective of this study was to evaluate the potential role of TNF-alpha in the onset of acute hepatitis in the Long-Evans Cinnamon (LEC) rat, an animal model for inherited copper (Cu) toxicosis. In LEC rats, Cu is accumulated in the liver with age, and clinical signs of acute hepatitis were observed as, icterus, reduced body weight, nasal bleeding, dehydration, and reduced food intake at 12 weeks of age. Cellular changes such as apoptosis in the liver were evident in these rats with increasing age. Positive TNF-alpha and TNFR1 immunostainings were observed in hepatocytes and Kupffer cells in LEC rats. Hepatic levels of caspase-3 activity, TNF-alpha mRNA, and protein were also increased in LEC rats from 6 to 12 weeks of age as compared with control Long-Evans (LE) rats. The neutralization of TNF-alpha by passive immunization or the inhibition of caspase activity can block the apoptotic process initiated by TNF-alpha. In this study, we evaluated the effects of passive immunization of LEC rats with weekly administration of anti-rat TNF-alpha on Cu-induced acute hepatitis. This treatment resulted in a reduction of the percentage of apoptotic cells in the liver, decreased activity of caspase-3, and also in down-regulation of the TNF-alpha gene expression. Thus, these results suggest a major role for TNF-alpha on the pathogenesis of Cu-induced acute hepatitis in LEC rats.