Role of TNF- Produced by Nonantigen-Specific Cells in a Fulminant Hepatitis Mouse Model

In previous studies, the mechanisms of acute liver injury and virus exclusion have been examined using a model wherein HBsAgspecific CTL are injected into HBsAg transgenic (Tg) mice. The importance of the role of TNFin virus exclusion was shown, but its role in liver injury was unclear. We crossed the TNFknockout mouse and HBsAg-Tg mouse to establish the HBsAgTg/TNFKO mouse, and examined the influence of TNFon liver injury. The severity of liver damage, as determined by serum alanine aminotransferase activity, was 100 times greater in HBsAg-Tg/TNF/ than in HBsAg-Tg/TNF/ mice after i.v. administration of 5 10 CTLs. This liver damage reached the peak of its severity within 24–48 h, and was restored 7 days later. Histopathological examination showed hepatocellular necrosis and inflammatory cell infiltrate 24 h after the CTL injection in HBsAg-Tg/TNF/ mice but not in HBsAg-Tg/TNF/ mice. The liver damage was fatal for all HBsAg-Tg/TNF/ mice that received 1.5 10 CTLs. In contrast, 1.5 10 CTLs could not kill the HBsAg-Tg/TNF/ mice. The TNFproduction level was enhanced after the CTL injection in not only intrahepatic macrophages but also other types of mononuclear cells from non-HBsAg-Tg/TNF/ mice. An adoptive transfer examination revealed that severe liver damage occurred in HBsAg-Tg/ TNF/ mice that had received mononuclear cells from TNF/ mice. In conclusion, the present study provides evidence that TNFproduced by intrahepatic non-Ag-specific inflammatory cells is critical in the development of lethal necroinflammatory liver disease. The Journal of Immunology, 2009, 182: 391–397.