| First Author | Ito H | Year | 2009 |
| Journal | J Immunol | Volume | 182 |
| Issue | 1 | Pages | 391-7 |
| PubMed ID | 19109170 | Mgi Jnum | J:142892 |
| Mgi Id | MGI:3822389 | Doi | 10.4049/jimmunol.182.1.391 |
| Citation | Ito H, et al. (2009) Role of TNF-alpha produced by nonantigen-specific cells in a fulminant hepatitis mouse model. J Immunol 182(1):391-7 |
| abstractText | In previous studies, the mechanisms of acute liver injury and virus exclusion have been examined using a model wherein HBsAg-specific CTL are injected into HBsAg transgenic (Tg) mice. The importance of the role of TNF-alpha in virus exclusion was shown, but its role in liver injury was unclear. We crossed the TNF-alpha knockout mouse and HBsAg-Tg mouse to establish the HBsAg-Tg/TNF-alpha KO mouse, and examined the influence of TNF-alpha on liver injury. The severity of liver damage, as determined by serum alanine aminotransferase activity, was approximately 100 times greater in HBsAg-Tg/TNF-alpha(+/+) than in HBsAg-Tg/TNF-alpha(-/-) mice after i.v. administration of 5 x 10(6) 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-alpha(+/+) mice but not in HBsAg-Tg/TNF-alpha(-/-) mice. The liver damage was fatal for all HBsAg-Tg/TNF-alpha(+/+) mice that received 1.5 x 10(7) CTLs. In contrast, 1.5 x 10(7) CTLs could not kill the HBsAg-Tg/TNF-alpha(-/-) mice. The TNF-alpha production level was enhanced after the CTL injection in not only intrahepatic macrophages but also other types of mononuclear cells from non-HBsAg-Tg/TNF-alpha(+/+) mice. An adoptive transfer examination revealed that severe liver damage occurred in HBsAg-Tg/TNF-alpha(-/-) mice that had received mononuclear cells from TNF-alpha(+/+) mice. In conclusion, the present study provides evidence that TNF-alpha produced by intrahepatic non-Ag-specific inflammatory cells is critical in the development of lethal necroinflammatory liver disease. |
