TNF α-induced ras activation due to ethanol promotes hepatocyte proliferation independently of liver injury in the mouse

Abstract

Tumor necrosis factor ␣ (TNF␣) has been shown to be both proapoptotic and mitogenic for hepatocytes and necessary for alcohol-induced liver injury. Ras, a known proto-oncogene, is very important in the regulation of cellular responses to TNF␣. Therefore, the purpose of this study was to investigate the role of Ras in alcohol-induced pathogenesis. Male C57Bl/6 mice were fed ethanol or high-fat control diet via intragastric cannulation for 4 weeks. Ras activity was increased significantly after 4 weeks of ethanol and correlated with an increase in pathologic features. However, in mice deficient in the receptor-type 1 for TNF␣ (TNFR1 -/-), ethanolinduced liver injury and the increase in Ras activity were significantly blunted compared with wild-type mice. Furthermore, it was demonstrated that H-, K-, and R-Ras isoforms were increased after ethanol exposure in wild-type mice. In TNFR1 -/-mice, R-Ras activity remained elevated by ethanol, whereas H-Ras and K-Ras activity was blunted significantly under these conditions. Interestingly, hepatocellular proliferation, which was elevated approximately fivefold after 4 weeks of chronic ethanol in wild-type mice, was also blunted in TNFR1 -/-mice given ethanol. Inhibition of Ras with adenovirus containing a dominant-negative Ras had no effect on ethanol-induced liver injury, but significantly blunted ethanol-induced hepatocyte proliferation by more than 50%. Overexpression of mitochondrial superoxide dismutase using recombinant adenovirus blunted lipid peroxidation and attenuated hepatic injury resulting from ethanol, but had no effect on Ras activation and hepatocyte proliferation caused by ethanol. In conclusion, these data support the hypotheses that hepatocellular oxidative stress leads to cell death and that TNF␣-induced Ras activation is important in hepatic proliferation in response to ethanolinduced liver injury. (HEPATOLOGY 2004;39:721-731.) R ecently, a critical role for TNF␣ in the early pathogenesis of alcohol-induced liver disease has been established. 1 TNF␣ is hypothesized to signal through TNFR1 to initiate a cascade of hepatocellular events, including mitochondrial oxidative stress, activation of stress kinases such as p42/44 and p38, and a number of other responses ultimately leading to cell death. However, TNF␣ has been described as both proapoptotic and mitogenic for hepatocytes. Thus, it is likely that investigation of downstream signal events from the TNF receptor may explain these apparent differences.Ras, a known proto-oncogene, is important in the regulation of cellular responses to TNF␣. Recently, it was shown that TNF␣-mediated signaling in hepatocytes involves activation of the Ras/mitogen activated protein kinase (MAPK) pathway. 2 Inhibition of Ras using a dominant-negative mutant nearly completely inhibited TNF␣-induced hepatocyte proliferation in culture. It has also been shown that TNF␣-mediated hepatocyte proliferation after partial hepatectomy is dependent on Ras activation. 3 Yet, it is unclear whether TNF␣ release caused by chronic eth...

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