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 |
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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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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)</description><identifier>ISSN: 0270-9139</identifier><identifier>EISSN: 1527-3350</identifier><identifier>DOI: 10.1002/hep.28282</identifier><identifier>PMID: 26458241</identifier><identifier>CODEN: HPTLD9</identifier><language>eng</language><publisher>United States: Wolters Kluwer Health, Inc</publisher><subject>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</subject><ispartof>Hepatology (Baltimore, Md.), 2016-01, Vol.63 (1), p.83-94</ispartof><rights>2015 by the American Association for the Study of Liver Diseases</rights><rights>2015 by the American Association for the Study of Liver Diseases.</rights><rights>2016 by the American Association for the Study of Liver Diseases</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5192-f84b486abdb5dba950dcc63fedc66e01a441ed9aa2bbac2794f58652af6d884c3</citedby><cites>FETCH-LOGICAL-c5192-f84b486abdb5dba950dcc63fedc66e01a441ed9aa2bbac2794f58652af6d884c3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fhep.28282$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fhep.28282$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26458241$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yoshio, Sachiyo</creatorcontrib><creatorcontrib>Sugiyama, Masaya</creatorcontrib><creatorcontrib>Shoji, Hirotaka</creatorcontrib><creatorcontrib>Mano, Yohei</creatorcontrib><creatorcontrib>Mita, Eiji</creatorcontrib><creatorcontrib>Okamoto, Toru</creatorcontrib><creatorcontrib>Matsuura, Yoshiharu</creatorcontrib><creatorcontrib>Okuno, Alato</creatorcontrib><creatorcontrib>Takikawa, Osamu</creatorcontrib><creatorcontrib>Mizokami, Masashi</creatorcontrib><creatorcontrib>Kanto, Tatsuya</creatorcontrib><title>Indoleamine‐2,3‐dioxygenase as an effector and an indicator of protective immune responses in patients with acute hepatitis B</title><title>Hepatology (Baltimore, Md.)</title><addtitle>Hepatology</addtitle><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)</description><subject>Acute Disease</subject><subject>Adult</subject><subject>Alanine</subject><subject>Alanine transaminase</subject><subject>Biomarkers - blood</subject><subject>Cell culture</subject><subject>Chemokines</subject><subject>Cross-Sectional Studies</subject><subject>CXCL10 protein</subject><subject>CXCL11 protein</subject><subject>Cytokines - blood</subject><subject>Dendritic cells</subject><subject>Dioxygenase</subject><subject>Female</subject><subject>Hepatitis</subject><subject>Hepatitis B</subject><subject>Hepatitis B - blood</subject><subject>Hepatitis B - enzymology</subject><subject>Hepatitis B - immunology</subject><subject>Hepatitis B virus</subject><subject>Hepatology</subject><subject>Humans</subject><subject>Immune clearance</subject><subject>Immune response</subject><subject>Indoleamine-Pyrrole 2,3,-Dioxygenase - physiology</subject><subject>Infectious diseases</subject><subject>Interferon</subject><subject>Liver</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Natural killer cells</subject><subject>T cell receptors</subject><subject>Tryptophan</subject><subject>α-Interferon</subject><subject>γ-Interferon</subject><issn>0270-9139</issn><issn>1527-3350</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkdFuFSEQhonR2GP1whcwJN5o4rbAAguXtam2SRO90GvCwmBpdmFddq3nTt_AZ_RJ5HiqFyYaMwkzDF_-DPMj9JiSI0oIO76C6YipGnfQhgrWNW0ryF20IawjjaatPkAPSrkmhGjO1H10wCQXinG6QV8vks8D2DEm-P7lG3vR1tPH_Hn7AZItgG3BNmEIAdyS51r73T0mH53dNXLA05yX-ho_AY7juCbAM5QppwKlgniyS4S0FHwTlyts3boArhPX7hILfvkQ3Qt2KPDoNh-i96_O3p2eN5dvXl-cnlw2TlDNmqB4z5W0ve-F760WxDsn2wDeSQmEWs4peG0t63vrWKd5EEoKZoP0SnHXHqJne9067scVymLGWBwMg02Q12Jo10kphejkf6CCcqUIbSv69A_0Oq9zqh8xVNO6bq468k-qE4RT1VJdqed7ys25lBmCmeY42nlrKDE7o01dm_lpdGWf3Cqu_Qj-N_nL2Qoc74GbOMD270rm_OztXvIHmcC0VQ</recordid><startdate>201601</startdate><enddate>201601</enddate><creator>Yoshio, Sachiyo</creator><creator>Sugiyama, Masaya</creator><creator>Shoji, Hirotaka</creator><creator>Mano, Yohei</creator><creator>Mita, Eiji</creator><creator>Okamoto, Toru</creator><creator>Matsuura, Yoshiharu</creator><creator>Okuno, Alato</creator><creator>Takikawa, Osamu</creator><creator>Mizokami, Masashi</creator><creator>Kanto, Tatsuya</creator><general>Wolters Kluwer Health, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7T5</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>H94</scope><scope>K9.</scope><scope>7X8</scope></search><sort><creationdate>201601</creationdate><title>Indoleamine‐2,3‐dioxygenase as an effector and an indicator of protective immune responses in patients with acute hepatitis B</title><author>Yoshio, Sachiyo ; Sugiyama, Masaya ; Shoji, Hirotaka ; Mano, Yohei ; Mita, Eiji ; Okamoto, Toru ; Matsuura, Yoshiharu ; Okuno, Alato ; Takikawa, Osamu ; Mizokami, Masashi ; Kanto, Tatsuya</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5192-f84b486abdb5dba950dcc63fedc66e01a441ed9aa2bbac2794f58652af6d884c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Acute Disease</topic><topic>Adult</topic><topic>Alanine</topic><topic>Alanine transaminase</topic><topic>Biomarkers - blood</topic><topic>Cell culture</topic><topic>Chemokines</topic><topic>Cross-Sectional Studies</topic><topic>CXCL10 protein</topic><topic>CXCL11 protein</topic><topic>Cytokines - blood</topic><topic>Dendritic cells</topic><topic>Dioxygenase</topic><topic>Female</topic><topic>Hepatitis</topic><topic>Hepatitis B</topic><topic>Hepatitis B - blood</topic><topic>Hepatitis B - enzymology</topic><topic>Hepatitis B - immunology</topic><topic>Hepatitis B virus</topic><topic>Hepatology</topic><topic>Humans</topic><topic>Immune clearance</topic><topic>Immune response</topic><topic>Indoleamine-Pyrrole 2,3,-Dioxygenase - physiology</topic><topic>Infectious diseases</topic><topic>Interferon</topic><topic>Liver</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Natural killer cells</topic><topic>T cell receptors</topic><topic>Tryptophan</topic><topic>α-Interferon</topic><topic>γ-Interferon</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yoshio, Sachiyo</creatorcontrib><creatorcontrib>Sugiyama, Masaya</creatorcontrib><creatorcontrib>Shoji, Hirotaka</creatorcontrib><creatorcontrib>Mano, Yohei</creatorcontrib><creatorcontrib>Mita, Eiji</creatorcontrib><creatorcontrib>Okamoto, Toru</creatorcontrib><creatorcontrib>Matsuura, Yoshiharu</creatorcontrib><creatorcontrib>Okuno, Alato</creatorcontrib><creatorcontrib>Takikawa, Osamu</creatorcontrib><creatorcontrib>Mizokami, Masashi</creatorcontrib><creatorcontrib>Kanto, Tatsuya</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><jtitle>Hepatology (Baltimore, Md.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yoshio, Sachiyo</au><au>Sugiyama, Masaya</au><au>Shoji, Hirotaka</au><au>Mano, Yohei</au><au>Mita, Eiji</au><au>Okamoto, Toru</au><au>Matsuura, Yoshiharu</au><au>Okuno, Alato</au><au>Takikawa, Osamu</au><au>Mizokami, Masashi</au><au>Kanto, Tatsuya</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Indoleamine‐2,3‐dioxygenase as an effector and an indicator of protective immune responses in patients with acute hepatitis B</atitle><jtitle>Hepatology (Baltimore, Md.)</jtitle><addtitle>Hepatology</addtitle><date>2016-01</date><risdate>2016</risdate><volume>63</volume><issue>1</issue><spage>83</spage><epage>94</epage><pages>83-94</pages><issn>0270-9139</issn><eissn>1527-3350</eissn><coden>HPTLD9</coden><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. (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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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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