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

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 fr...

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Veröffentlicht in:Hepatology (Baltimore, Md.) Md.), 2016-01, Vol.63 (1), p.83-94
Hauptverfasser: Yoshio, Sachiyo, Sugiyama, Masaya, Shoji, Hirotaka, Mano, Yohei, Mita, Eiji, Okamoto, Toru, Matsuura, Yoshiharu, Okuno, Alato, Takikawa, Osamu, Mizokami, Masashi, Kanto, Tatsuya
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container_issue 1
container_start_page 83
container_title Hepatology (Baltimore, Md.)
container_volume 63
creator Yoshio, Sachiyo
Sugiyama, Masaya
Shoji, Hirotaka
Mano, Yohei
Mita, Eiji
Okamoto, Toru
Matsuura, Yoshiharu
Okuno, Alato
Takikawa, Osamu
Mizokami, Masashi
Kanto, Tatsuya
description 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. (Hepatology 2016;63:83–94)
doi_str_mv 10.1002/hep.28282
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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. 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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. 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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. (Hepatology 2016;63:83–94)</abstract><cop>United States</cop><pub>Wolters Kluwer Health, Inc</pub><pmid>26458241</pmid><doi>10.1002/hep.28282</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record>
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source MEDLINE; EZB-FREE-00999 freely available EZB journals; Wiley Online Library All Journals
subjects Acute Disease
Adult
Alanine
Alanine transaminase
Biomarkers - blood
Cell culture
Chemokines
Cross-Sectional Studies
CXCL10 protein
CXCL11 protein
Cytokines - blood
Dendritic cells
Dioxygenase
Female
Hepatitis
Hepatitis B
Hepatitis B - blood
Hepatitis B - enzymology
Hepatitis B - immunology
Hepatitis B virus
Hepatology
Humans
Immune clearance
Immune response
Indoleamine-Pyrrole 2,3,-Dioxygenase - physiology
Infectious diseases
Interferon
Liver
Male
Middle Aged
Natural killer cells
T cell receptors
Tryptophan
α-Interferon
γ-Interferon
title Indoleamine‐2,3‐dioxygenase as an effector and an indicator of protective immune responses in patients with acute hepatitis B
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