title: Upregulation of indoleamine 2,3-dioxygenase in hepatocyte during acute hepatitis caused by hepatitis B virus-specific cytotoxic T lymphocytes in vivo.
abstract: OBJECTIVE
  Indoleamine-2,3-dioxygenase (IDO) is a tryptophan-catabolizing enzyme inducing suppression of T-cell function and immune tolerance. In hepatitis B virus (HBV) transgenic (Tg) mice, the adoptive transfer of HBV-specific cytotoxic T lymphocytes (CTL) causes a necroinflammatory liver disease that is histologically similar to acute viral hepatitis in man. The present study aimed to determine IDO expression in the liver and hepatocytes during an acute hepatitis model.
  
  
  METHODS
  Serum l-kynurenine (l-Kyn) concentration in HBV Tg mice administered with HBV-specific CTL was measured over time, together with serum levels of alanine aminotransferase (ALT). Furthermore, we examined the expression of IDO in the total liver and isolated hepatocytes of HBV Tg mice after CTL injection using immunohistochemical analysis and reverse-transcription polymerase chain reaction (PCR).
  
  
  RESULTS
  In HBV Tg mice, HBV-specific CTL induced, over the course of several days, a chronic increase in serum l-Kyn levels, which was associated with a sustained enhancement of liver IDO activity. In particular, IDO expression was enhanced in the liver parenchymal cells (hepatocytes) after HBV-specific CTL injection both in immunohistochemical analysis and in reverse-transcription PCR. Moreover, murine recombinant interferon-gamma (IFN-gamma) directly increased the IDO expression in primary hepatocytes in vitro.
  
  
  CONCLUSIONS
  Cytotoxic T lymphocytes transduction results in the upregulation of IDO, which might downregulate T-cell responsiveness. Our findings provide evidence that hepatocyte itself expresses IDO and increases levels of l-Kyn in the blood in acute lethal hepatitis of mice. These data indicate that HBV infection facilitates the induction of IDO in response to proinflammatory cytokines, particularly IFN-gamma.
authors.affiliation: Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Iwamoto
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Ito
authors.forename: Kazuki
authors.initials: K
authors.lastname: Ando
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Ishikawa
authors.forename: Akira
authors.initials: A
authors.lastname: Hara
authors.forename: Ayako
authors.initials: A
authors.lastname: Taguchi
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Saito
authors.forename: Masao
authors.initials: M
authors.lastname: Takemura
authors.forename: Michio
authors.initials: M
authors.lastname: Imawari
authors.forename: Hisataka
authors.initials: H
authors.lastname: Moriwaki
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Seishima
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D006515:Hepatitis B virus / Q000276:immunology*; D006524:Hepatitis, Viral, Animal / Q000201:enzymology* / Q000209:etiology* / Q000276:immunology; D022781:Hepatocytes / Q000378:metabolism; D007150:Immunohistochemistry; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D007371:Interferon-gamma / Q000378:metabolism; D007737:Kynurenine / Q000097:blood; D051379:Mice; D008822:Mice, Transgenic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000637:transplantation*; D015854:Up-Regulation
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007737:Kynurenine; D007371:Interferon-gamma; D000410:Alanine Transaminase