Indoleamine 2,3-dioxygenase 1 deficiency attenuates CCl4-induced fibrosis through Th17 cells down-regulation and tryptophan 2,3-dioxygenase compensation.
Indoleamine 2,3-dioxygenase 1 deficiency attenuates CCl4-induced fibrosis through Th17 cells down-regulation and tryptophan 2,3-dioxygenase compensation.
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吲哚胺 2,3-双加氧酶 1 缺陷通过 Th17 细胞下调和色氨酸 2,3-双加氧酶补偿减轻 CCl4 诱导的纤维化
DOI：
10.18632/oncotarget.17119
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发表时间：
2017-06-20
期刊：
影响因子：
--
通讯作者：
Lv Z
中科院分区：
文献类型：
--
作者：
Zhong W;Gao L;Zhou Z;Lin H;Chen C;Huang P;Huang W;Zhou C;Huang S;Nie L;Liu Y;Chen Y;Zhou D;Lv Z
吲哚胺2，3-双加氧酶1（IDO 1）是色氨酸沿着犬尿氨酸途径代谢的细胞内限速酶，随后介导免疫应答;然而，IDO 1在肝纤维化和肝硬化中的作用仍不清楚。在这项研究中，我们研究了IDO 1在肝纤维化和肝硬化发展中的作用。入选B型肝炎病毒诱导的肝硬化患者和健康志愿者。对于动物，使用四氯化碳（CCl 4）在野生型和IDO 1敲除小鼠中建立肝纤维化。此外，向WT纤维化小鼠施用IDO 1抑制剂（1-甲基-D-色氨酸）。在临床受试者和肝纤维化小鼠中，肝脏病变与血清IDO 1水平呈正相关。肝硬化患者血清IDO 1水平与肝硬度值呈正相关。值得注意的是，IDO 1基因敲除小鼠受到保护，免受CCl 4诱导的肝纤维化，这反映在血清丙氨酸转氨酶和天冬氨酸转氨酶水平不变，胶原沉积、α-平滑肌肌动蛋白表达和凋亡细胞死亡率降低。另一方面，色氨酸2，3-双加氧酶（TDO），另一种系统性色氨酸代谢酶，表现出代偿性增加IDO 1缺乏的结果。此外，肝脏白细胞介素-17 α，一种辅助性T细胞17（Th 17）的特征性细胞因子，和下游细胞因子的mRNA水平在IDO 1-/-模型小鼠中显示较低的表达。IDO 1似乎是肝脏病变的潜在标志，其缺乏可保护小鼠免受由Th 17细胞下调和TDO补偿介导的CCl 4诱导的纤维化。
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 (CCl4) 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 CCl4-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 CCl4-induced fibrosis mediated by Th17 cells down-regulation and TDO compensation.
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影响因子：
14.8
作者：
Keller, Tracy L.;Zocco, Davide;Sundrud, Mark S.;Hendrick, Margaret;Edenius, Maja;Yum, Jinah;Kim, Yeon-Jin;Lee, Hak-Kyo;Cortese, Joseph F.;Wirth, Dyann F.;Dignam, John David;Rao, Anjana;Yeo, Chang-Yeol;Mazitschek, Ralph;Whitman, Malcolm
通讯作者：
Whitman, Malcolm
影响因子：
12.6
作者：
Rockey, Don C.
通讯作者：
Rockey, Don C.
影响因子：
3.7
作者：
Ogiso H;Ito H;Ando T;Arioka Y;Kanbe A;Ando K;Ishikawa T;Saito K;Hara A;Moriwaki H;Shimizu M;Seishima M
通讯作者：
Seishima M
影响因子：
6.3
作者：
Higashitani, Koyo;Kanto, Tatsuya;Takehara, Tetsuo
通讯作者：
Takehara, Tetsuo
影响因子：
29.4
作者：
Meng F;Wang K;Aoyama T;Grivennikov SI;Paik Y;Scholten D;Cong M;Iwaisako K;Liu X;Zhang M;Österreicher CH;Stickel F;Ley K;Brenner DA;Kisseleva T
通讯作者：
Kisseleva T