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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Weichao Zhong1,2,*, Lei Gao1,*, Zhenting Zhou1, Haiyan Lin1, Chun Chen3, Peng Huang1, Weiliang Huang1, Chuying Zhou1, Shaohui Huang1, Linghui Nie1, Ye Liu4, Youming Chen4, Daqiao Zhou2 and Zhiping Lv1
1School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China
2Department of Liver Diseases, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong, 518033, China
3Department of Pharmacology, Shantou University Medical College, Shantou, Guangdong, 515041, China
4The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, 510630, China
*These authors contributed equally to this work
Zhiping Lv, email: email@example.com
Daqiao Zhou, email: firstname.lastname@example.org
Keywords: indoleamine 2,3-dioxygenase 1, liver fibrosis, T helper 17 cells, tryptophan 2,3-dioxygenase, 1-methyl-D-tryptophan
Received: November 04, 2016 Accepted: April 03, 2017 Published: April 15, 2017
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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