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

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

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
Volume182
Issue number1
Publication statusPublished - 01-01-2009
Externally publishedYes

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Hepatitis B Surface Antigens
Hepatitis
Transgenic Mice
Liver
Wounds and Injuries
Viruses
Injections
Adoptive Transfer
Alanine Transaminase
Knockout Mice
Liver Diseases
Necrosis
Macrophages

All Science Journal Classification (ASJC) codes

  • Immunology

Cite this

Ito, H., Ando, K., Ishikawa, T., Saito, K., Takemura, M., Imawari, M., ... Seishima, M. (2009). Role of TNF-α produced by nonantigen-specific cells in a fulminant hepatitis mouse model. Journal of Immunology, 182(1), 391-397.
Ito, Hiroyasu ; Ando, Kazuki ; Ishikawa, Tetsuya ; Saito, Kuniaki ; Takemura, Masao ; Imawari, Michio ; Moriwaki, Hisataka ; Seishima, Mitsuru. / Role of TNF-α produced by nonantigen-specific cells in a fulminant hepatitis mouse model. In: Journal of Immunology. 2009 ; Vol. 182, No. 1. pp. 391-397.
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Ito, H, Ando, K, Ishikawa, T, Saito, K, Takemura, M, Imawari, M, Moriwaki, H & Seishima, M 2009, 'Role of TNF-α produced by nonantigen-specific cells in a fulminant hepatitis mouse model', Journal of Immunology, vol. 182, no. 1, pp. 391-397.

Role of TNF-α produced by nonantigen-specific cells in a fulminant hepatitis mouse model. / Ito, Hiroyasu; Ando, Kazuki; Ishikawa, Tetsuya; Saito, Kuniaki; Takemura, Masao; Imawari, Michio; Moriwaki, Hisataka; Seishima, Mitsuru.

In: Journal of Immunology, Vol. 182, No. 1, 01.01.2009, p. 391-397.

Research output: Contribution to journalArticle

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AU - Ito, Hiroyasu

AU - Ando, Kazuki

AU - Ishikawa, Tetsuya

AU - Saito, Kuniaki

AU - Takemura, Masao

AU - Imawari, Michio

AU - Moriwaki, Hisataka

AU - Seishima, Mitsuru

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Ito H, Ando K, Ishikawa T, Saito K, Takemura M, Imawari M et al. Role of TNF-α produced by nonantigen-specific cells in a fulminant hepatitis mouse model. Journal of Immunology. 2009 Jan 1;182(1):391-397.