Upregulation of indoleamine 2,3-dioxygenase in hepatocyte during acute hepatitis caused by hepatitis B virus-specific cytotoxic T lymphocytes in vivo

Naoki Iwamoto, Hiroyasu Ito, Kazuki Ando, Tetsuya Ishikawa, Akira Hara, Ayako Taguchi, Kuniaki Saito, Masao Takemura, Michio Imawari, Hisataka Moriwaki, Mitsuru Seishima

Research output: Contribution to journalArticle

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Abstract

Background/Aims: 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-γ (IFN-γ) 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-γ.

Original languageEnglish
Pages (from-to)277-283
Number of pages7
JournalLiver International
Volume29
Issue number2
DOIs
Publication statusPublished - 19-01-2009
Externally publishedYes

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Indoleamine-Pyrrole 2,3,-Dioxygenase
Cytotoxic T-Lymphocytes
Hepatitis B virus
Hepatitis
Hepatocytes
Up-Regulation
Transgenic Mice
Kynurenine
Liver
Interferons
Reverse Transcription
Serum
Murine hepatitis virus
T-Lymphocytes
Polymerase Chain Reaction
Immune Tolerance
Injections
Adoptive Transfer
Virus Diseases
Alanine Transaminase

All Science Journal Classification (ASJC) codes

  • Hepatology

Cite this

Iwamoto, Naoki ; Ito, Hiroyasu ; Ando, Kazuki ; Ishikawa, Tetsuya ; Hara, Akira ; Taguchi, Ayako ; Saito, Kuniaki ; Takemura, Masao ; Imawari, Michio ; Moriwaki, Hisataka ; Seishima, Mitsuru. / Upregulation of indoleamine 2,3-dioxygenase in hepatocyte during acute hepatitis caused by hepatitis B virus-specific cytotoxic T lymphocytes in vivo. In: Liver International. 2009 ; Vol. 29, No. 2. pp. 277-283.
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title = "Upregulation of indoleamine 2,3-dioxygenase in hepatocyte during acute hepatitis caused by hepatitis B virus-specific cytotoxic T lymphocytes in vivo",
abstract = "Background/Aims: 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-γ (IFN-γ) 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-γ.",
author = "Naoki Iwamoto and Hiroyasu Ito and Kazuki Ando and Tetsuya Ishikawa and Akira Hara and Ayako Taguchi and Kuniaki Saito and Masao Takemura and Michio Imawari and Hisataka Moriwaki and Mitsuru Seishima",
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Iwamoto, N, Ito, H, Ando, K, Ishikawa, T, Hara, A, Taguchi, A, Saito, K, Takemura, M, Imawari, M, Moriwaki, H & Seishima, M 2009, 'Upregulation of indoleamine 2,3-dioxygenase in hepatocyte during acute hepatitis caused by hepatitis B virus-specific cytotoxic T lymphocytes in vivo', Liver International, vol. 29, no. 2, pp. 277-283. https://doi.org/10.1111/j.1478-3231.2008.01748.x

Upregulation of indoleamine 2,3-dioxygenase in hepatocyte during acute hepatitis caused by hepatitis B virus-specific cytotoxic T lymphocytes in vivo. / Iwamoto, Naoki; Ito, Hiroyasu; Ando, Kazuki; Ishikawa, Tetsuya; Hara, Akira; Taguchi, Ayako; Saito, Kuniaki; Takemura, Masao; Imawari, Michio; Moriwaki, Hisataka; Seishima, Mitsuru.

In: Liver International, Vol. 29, No. 2, 19.01.2009, p. 277-283.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Upregulation of indoleamine 2,3-dioxygenase in hepatocyte during acute hepatitis caused by hepatitis B virus-specific cytotoxic T lymphocytes in vivo

AU - Iwamoto, Naoki

AU - Ito, Hiroyasu

AU - Ando, Kazuki

AU - Ishikawa, Tetsuya

AU - Hara, Akira

AU - Taguchi, Ayako

AU - Saito, Kuniaki

AU - Takemura, Masao

AU - Imawari, Michio

AU - Moriwaki, Hisataka

AU - Seishima, Mitsuru

PY - 2009/1/19

Y1 - 2009/1/19

N2 - Background/Aims: 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-γ (IFN-γ) 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-γ.

AB - Background/Aims: 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-γ (IFN-γ) 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-γ.

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DO - 10.1111/j.1478-3231.2008.01748.x

M3 - Article

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SP - 277

EP - 283

JO - Liver International

JF - Liver International

SN - 1478-3223

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