Indoleamine-2,3-dioxygenase as an effector and an indicator of protective immune responses in patients with acute hepatitis B

Sachiyo Yoshio, Masaya Sugiyama, Hirotaka Shoji, Yohei Mano, Eiji Mita, Toru Okamoto, Yoshiharu Matsuura, Alato Okuno, Osamu Takikawa, Masashi Mizokami, Tatsuya Kanto

Research output: Contribution to journalArticle

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Abstract

Indoleamine-2, 3-dioxygenase (IDO), an interferon-γ-inducible enzyme catalyzing tryptophan into kynurenine, exerts dual functions in infectious diseases, acting as a suppressor of intracellular pathogens and as an immune regulator. We explored the roles of IDO in hepatitis B virus (HBV) clearance from infected patients. We examined IDO activity, serum chemokines, and cytokines in 53 HBV-positive patients (25 acute hepatitis, 14 chronic hepatitis, and 14 hepatic flare) and 14 healthy volunteers. In order to clarify the mechanisms of IDO induction and its impact on HBV replication, we used a culture model consisting of human natural killer cells, plasmacytoid dendritic cells, and HBV-transfected Huh7 cells in which IDO expression is controlled. A robust activation of IDO with an inverse correlation of alanine aminotransferase at the peak was observed in patients with acute hepatitis B but not in patients with hepatic flare. In acute hepatitis patients who eventually cleared HBV, IDO activity, chemokine (C-X-C motif) ligand 9 (CXCL9), CXCL10, and CXCL11 increased at the peak of alanine aminotransferase. In contrast, in patients with hepatic flare, IDO activity remained at lower levels during the observation period, regardless of the surge of CXCL9, CXCL10, and CXCL11 at the alanine aminotransferase peak. Natural killer cells and plasmacytoid dendritic cells synergistically produced interferon-γ and interferon-α, thereby enhancing IDO activity and HBV suppression in Huh7 cells. Such suppressor capacity of IDO on HBV was abrogated in IDO-knockout cells and recovered by the reinduction of IDO in the cells. Conclusion: IDO is an anti-HBV effector and an indicator of subsequent immune responses operative during the early phase of infection; its activity is boosted by coexisting natural killer cells and plasmacytoid dendritic cells.

Original languageEnglish
Pages (from-to)83-94
Number of pages12
JournalHepatology
Volume63
Issue number1
DOIs
Publication statusPublished - Jan 1 2016

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Indoleamine-Pyrrole 2,3,-Dioxygenase
Hepatitis B
Hepatitis B virus
Alanine Transaminase
Natural Killer Cells
Dendritic Cells
Interferons
Hepatitis
Liver
Ligands
Kynurenine
CXC Chemokines
Chronic Hepatitis
Virus Replication
Chemokines
Tryptophan

All Science Journal Classification (ASJC) codes

  • Hepatology

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Indoleamine-2,3-dioxygenase as an effector and an indicator of protective immune responses in patients with acute hepatitis B. / Yoshio, Sachiyo; Sugiyama, Masaya; Shoji, Hirotaka; Mano, Yohei; Mita, Eiji; Okamoto, Toru; Matsuura, Yoshiharu; Okuno, Alato; Takikawa, Osamu; Mizokami, Masashi; Kanto, Tatsuya.

In: Hepatology, Vol. 63, No. 1, 01.01.2016, p. 83-94.

Research output: Contribution to journalArticle

Yoshio, S, Sugiyama, M, Shoji, H, Mano, Y, Mita, E, Okamoto, T, Matsuura, Y, Okuno, A, Takikawa, O, Mizokami, M & Kanto, T 2016, 'Indoleamine-2,3-dioxygenase as an effector and an indicator of protective immune responses in patients with acute hepatitis B', Hepatology, vol. 63, no. 1, pp. 83-94. https://doi.org/10.1002/hep.28282
Yoshio, Sachiyo ; Sugiyama, Masaya ; Shoji, Hirotaka ; Mano, Yohei ; Mita, Eiji ; Okamoto, Toru ; Matsuura, Yoshiharu ; Okuno, Alato ; Takikawa, Osamu ; Mizokami, Masashi ; Kanto, Tatsuya. / Indoleamine-2,3-dioxygenase as an effector and an indicator of protective immune responses in patients with acute hepatitis B. In: Hepatology. 2016 ; Vol. 63, No. 1. pp. 83-94.
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AU - Mano, Yohei

AU - Mita, Eiji

AU - Okamoto, Toru

AU - Matsuura, Yoshiharu

AU - Okuno, Alato

AU - Takikawa, Osamu

AU - Mizokami, Masashi

AU - Kanto, Tatsuya

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