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Indoleamine 2,3-dioxygenase 1 deficiency attenuates CCl(4)-induced fibrosis through Th17 cells down-regulation and tryptophan 2,3-dioxygenase compensation

Indoleamine 2,3-dioxygenase 1 (IDO1) is an intracellular rate-limiting enzyme in the metabolism of tryptophan along the kynurenine pathway, subsequently mediating the immune response; however, the role of IDO1 in liver fibrosis and cirrhosis is still unclear. In this study, we investigated the role...

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Autores principales: Zhong, Weichao, Gao, Lei, Zhou, Zhenting, Lin, Haiyan, Chen, Chun, Huang, Peng, Huang, Weiliang, Zhou, Chuying, Huang, Shaohui, Nie, Linghui, Liu, Ye, Chen, Youming, Zhou, Daqiao, Lv, Zhiping
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5522192/
https://www.ncbi.nlm.nih.gov/pubmed/28465467
http://dx.doi.org/10.18632/oncotarget.17119
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author Zhong, Weichao
Gao, Lei
Zhou, Zhenting
Lin, Haiyan
Chen, Chun
Huang, Peng
Huang, Weiliang
Zhou, Chuying
Huang, Shaohui
Nie, Linghui
Liu, Ye
Chen, Youming
Zhou, Daqiao
Lv, Zhiping
author_facet Zhong, Weichao
Gao, Lei
Zhou, Zhenting
Lin, Haiyan
Chen, Chun
Huang, Peng
Huang, Weiliang
Zhou, Chuying
Huang, Shaohui
Nie, Linghui
Liu, Ye
Chen, Youming
Zhou, Daqiao
Lv, Zhiping
author_sort Zhong, Weichao
collection PubMed
description Indoleamine 2,3-dioxygenase 1 (IDO1) is an intracellular rate-limiting enzyme in the metabolism of tryptophan along the kynurenine pathway, subsequently mediating the immune response; however, the role of IDO1 in liver fibrosis and cirrhosis is still unclear. In this study, we investigated the role of IDO1 in the development of hepatic fibrosis and cirrhosis. Patients with hepatitis B virus-induced cirrhosis and healthy volunteers were enrolled. For animals, carbon tetrachloride (CCl(4)) was used to establish liver fibrosis in wild-type and IDO1 knockout mice. Additionally, an IDO1 inhibitor (1-methyl-(D)-tryptophan) was administered to WT fibrosis mice. Liver lesions were positively correlated with serum IDO1 levels in both the clinical subjects and hepatic fibrosis mice. A positive correlation between serum IDO1 levels and liver stiffness values was found in the cirrhosis patients. Notably, IDO1 knockout mice were protected from CCl(4)-induced liver fibrosis, as reflected by unchanged serum alanine transaminase and aspartate transaminase levels and lower collagen deposition, α-smooth muscle actin expression and apoptotic cell death rates. On the other hand, tryptophan 2,3-dioxygenase (TDO), another systemic tryptophan metabolism enzyme, exhibited a compensatory increase as a result of IDO1 deficiency. Moreover, hepatic interleukin-17a, a characteristic cytokine of T helper 17 (Th17) cells, and downstream cytokines’ mRNA levels showed lower expression in the IDO1(–/–) model mice. IDO1 appears to be a potential hallmark of liver lesions, and its deficiency protects mice from CCl(4)-induced fibrosis mediated by Th17 cells down-regulation and TDO compensation.
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spelling pubmed-55221922017-08-21 Indoleamine 2,3-dioxygenase 1 deficiency attenuates CCl(4)-induced fibrosis through Th17 cells down-regulation and tryptophan 2,3-dioxygenase compensation Zhong, Weichao Gao, Lei Zhou, Zhenting Lin, Haiyan Chen, Chun Huang, Peng Huang, Weiliang Zhou, Chuying Huang, Shaohui Nie, Linghui Liu, Ye Chen, Youming Zhou, Daqiao Lv, Zhiping Oncotarget Research Paper Indoleamine 2,3-dioxygenase 1 (IDO1) is an intracellular rate-limiting enzyme in the metabolism of tryptophan along the kynurenine pathway, subsequently mediating the immune response; however, the role of IDO1 in liver fibrosis and cirrhosis is still unclear. In this study, we investigated the role of IDO1 in the development of hepatic fibrosis and cirrhosis. Patients with hepatitis B virus-induced cirrhosis and healthy volunteers were enrolled. For animals, carbon tetrachloride (CCl(4)) was used to establish liver fibrosis in wild-type and IDO1 knockout mice. Additionally, an IDO1 inhibitor (1-methyl-(D)-tryptophan) was administered to WT fibrosis mice. Liver lesions were positively correlated with serum IDO1 levels in both the clinical subjects and hepatic fibrosis mice. A positive correlation between serum IDO1 levels and liver stiffness values was found in the cirrhosis patients. Notably, IDO1 knockout mice were protected from CCl(4)-induced liver fibrosis, as reflected by unchanged serum alanine transaminase and aspartate transaminase levels and lower collagen deposition, α-smooth muscle actin expression and apoptotic cell death rates. On the other hand, tryptophan 2,3-dioxygenase (TDO), another systemic tryptophan metabolism enzyme, exhibited a compensatory increase as a result of IDO1 deficiency. Moreover, hepatic interleukin-17a, a characteristic cytokine of T helper 17 (Th17) cells, and downstream cytokines’ mRNA levels showed lower expression in the IDO1(–/–) model mice. IDO1 appears to be a potential hallmark of liver lesions, and its deficiency protects mice from CCl(4)-induced fibrosis mediated by Th17 cells down-regulation and TDO compensation. Impact Journals LLC 2017-04-15 /pmc/articles/PMC5522192/ /pubmed/28465467 http://dx.doi.org/10.18632/oncotarget.17119 Text en Copyright: © 2017 Zhong et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (http://creativecommons.org/licenses/by/3.0/) (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Zhong, Weichao
Gao, Lei
Zhou, Zhenting
Lin, Haiyan
Chen, Chun
Huang, Peng
Huang, Weiliang
Zhou, Chuying
Huang, Shaohui
Nie, Linghui
Liu, Ye
Chen, Youming
Zhou, Daqiao
Lv, Zhiping
Indoleamine 2,3-dioxygenase 1 deficiency attenuates CCl(4)-induced fibrosis through Th17 cells down-regulation and tryptophan 2,3-dioxygenase compensation
title Indoleamine 2,3-dioxygenase 1 deficiency attenuates CCl(4)-induced fibrosis through Th17 cells down-regulation and tryptophan 2,3-dioxygenase compensation
title_full Indoleamine 2,3-dioxygenase 1 deficiency attenuates CCl(4)-induced fibrosis through Th17 cells down-regulation and tryptophan 2,3-dioxygenase compensation
title_fullStr Indoleamine 2,3-dioxygenase 1 deficiency attenuates CCl(4)-induced fibrosis through Th17 cells down-regulation and tryptophan 2,3-dioxygenase compensation
title_full_unstemmed Indoleamine 2,3-dioxygenase 1 deficiency attenuates CCl(4)-induced fibrosis through Th17 cells down-regulation and tryptophan 2,3-dioxygenase compensation
title_short Indoleamine 2,3-dioxygenase 1 deficiency attenuates CCl(4)-induced fibrosis through Th17 cells down-regulation and tryptophan 2,3-dioxygenase compensation
title_sort indoleamine 2,3-dioxygenase 1 deficiency attenuates ccl(4)-induced fibrosis through th17 cells down-regulation and tryptophan 2,3-dioxygenase compensation
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5522192/
https://www.ncbi.nlm.nih.gov/pubmed/28465467
http://dx.doi.org/10.18632/oncotarget.17119
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