Kynurenine production mediated by indoleamine 2,3-dioxygenase aggravates liver injury in HBV-specific CTL-induced fulminant hepatitis

Hirofumi Ohtaki, Hiroyasu Ito, Kazuki Ando, Tetsuya Ishikawa, Masato Hoshi, Tatsuya Ando, Manabu Takamatsu, Akira Hara, Hisataka Moriwaki, Kuniaki Saito, Mitsuru Seishima

研究成果: ジャーナルへの寄稿学術論文査読

11 被引用数 (Scopus)


Indoleamine 2,3-dioxygenase (IDO), an enzyme that is ubiquitously distributed in mammalian tissues and cells, converts tryptophan to kynurenine, and is also known as a key molecule that promotes apoptosis in lymphocytes and neurons. In this study, we established hepatitis B virus (HBV)-transgenic (Tg)/IDO-knockout (KO) mice and examined the influence of IDO in a murine fulminant hepatitis model induced by HBV-specific cytotoxic T lymphocytes (CTL). An increase of IDO expression in the livers of HBV-Tg/IDO-wild-type (WT) mice administered HBV-specific CTL was confirmed by real-time polymerase chain reaction, western blotting, and evaluating IDO activity. Plasma alanine aminotransferase (ALT) levels in HBV-Tg/IDO-KO mice after HBV-specific CTL injection significantly decreased compared with those in HBV-Tg/IDO-WT mice. An inhibitor of IDO, 1-methyl- d-tryptophan (1-MT), could also attenuated the observed liver injury induced by this HBV-specific CTL. The expression levels of cytokine and chemokine mRNAs in the livers of HBV-Tg/IDO-WT mice were higher than those in the livers of HBV-Tg/IDO-KO mice. The administration of kynurenine aggravated the liver injury in HBV-Tg/IDO-KO mice injected with HBV-specific CTL. Simultaneous injection of recombinant murine interferon (IFN-γ) and kynurenine also increased the ALT levels in HBV-Tg/IDO-KO mice. The liver injury induced by IFN-γ and kynurenine was improved in HBV-Tg/tumor necrosis factor-α-KO mice. Conclusion: Kynurenine and IFN-γ induced by the administration with HBV-specific CTL are cooperatively involved in the progression of liver injury in acute hepatitis model. Our results may lead to a new therapy for the acute liver injury caused by HBV infection.

ジャーナルBiochimica et Biophysica Acta - Molecular Basis of Disease
出版ステータス出版済み - 09-2014

All Science Journal Classification (ASJC) codes

  • 分子医療
  • 分子生物学


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