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

Abstract

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