Role of TNF-α produced by nonantigen-specific cells in a fulminant hepatitis mouse model

Hiroyasu Ito, Kazuki Ando, Tetsuya Ishikawa, Kuniaki Saito, Masao Takemura, Michio Imawari, Hisataka Moriwaki, Mitsuru Seishima

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34 Citations (Scopus)


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 TNF-α in virus exclusion was shown, but its role in liver injury was unclear. We crossed the TNF-α knockout mouse and HBsAg-Tg mouse to establish the HBsAg-Tg/TNF-αKO mouse, and examined the influence of TNF-αon liver injury. The severity of liver damage, as determined by serum alanine aminotransferase activity, was ∼100 times greater in HBsAg-Tg/TNF-α+/+ than in HBsAg-Tg/TNF-α-/- mice after i.v. administration of 5 × 106 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-α+/+ mice but not in HBsAg-Tg/TNF-α -/- mice. The liver damage was fatal for all HBsAg-Tg/TNF- α+/+ mice that received 1.5 × 107 CTLs. In contrast, 1.5 × 107 CTLs could not kill the HBsAg-Tg/TNF-α+/+ mice. The TNF-α 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-α+/+ mice. An adoptive transfer examination revealed that severe liver damage occurred in HBsAg-Tg/ TNF-α-/- mice that had received mononuclear cells from TNF-α+/+ mice. In conclusion, the present study provides evidence that TNF-α produced by intrahepatic non-Ag-specific inflammatory cells is critical in the development of lethal necroinflammatory liver disease.

Original languageEnglish
Pages (from-to)391-397
Number of pages7
JournalJournal of Immunology
Issue number1
Publication statusPublished - 01-01-2009
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology


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