The protective or damaging effect of Tumor necrosis factor-α in acute liver injury is concentration-dependent

Background: Inflammatory cytokine is important in modulating injured diseases. Tumor necrosis factor-alpha (TNF-alpha), one of potent inflammatory cytokines, plays a dominant role in host defense reaction. However, the concrete effect of TNF-alpha on acute liver injury is totally unclear. Here we reported the concrete effect and possible mechanisms of TNF-alpha on acute liver injury induced by carbon tetrachloride (CCl4). Methods: SD male rats were equally divided into nine groups. CCl4 (1 ml/kg) was subcutaneously injected into the rats. Enbrel, a TNF-alpha inhibitor, were intraperitoneally injected at dose of 0, 0.25, 0.5, 1, 2, 4 or 8 mg/kg 15 min before the CCl4 injection. 24 h later, rats were sacrificed. Serum ALT and AST were measured with an autoanalyzer. Serum TNF-alpha were measured by ELISA. HE staining was used to observe the liver tissue morphology. Hepatocellular apoptosis were tested by immunochemistry and Tunnel kit. Inflammatory factors, involve IL-4, IL-6, IL-8, IL-beta and IFN-gamma were detected by RT-PCR. The NF-kappa B signal pathway and anti-apoptotic genes include Bcl-XL, FHC, XIAP and Bcl-2 were measured by western-blotting and RT-PCR. Results: The change of liver function presented an obvious V shape in the whole process of persistently increased Enbrel. As Enbrel was increased gradually from 0 to 1 mg/kg, serum TNF-alpha were blocked, ALT and AST were gradually decreased as TNF-alpha as well as the numbers of hepatocellular apoptosis, and were declined to the minimum at 1 mg/kg Enbrel. As Enbrel was increased gradually from 1 to 8 mg/kg, ALT, AST and hepatocellular apoptosis were increased instead, and reached to the maximum at 8 mg/kg Enbrel. HE showed that the seriousness of hepatocellular steatosis was the most at 8 mg/kg Enbrel, and second at 0 mg/kg, the weakest at 1 mg/kg in the acute liver injury. Western-blotting and RT-PCR showed NF-kappa B, p-I kappa B alpha and antiapoptotic genes include Bcl-XL, FHC, XIAP, Bcl-2 were decreased as TNF-alpha was blocked by increased Enbrel. Conclusion: Our results suggested that TNF-alpha had a dual role in acute liver injury. It was regulated might via the corporate effect of NF-kappa B signal pawahway and anti-apoptosis. Meanwhile, our findings provide a reference for clinical treatment of acute liver injury.