Indoleamine 2,3-dioxygenase 1 deficiency attenuates CCl4-induced fibrosis through Th17 cells down-regulation and tryptophan 2,3-dioxygenase compensation

Abstract

// Weichao Zhong 1, 2, * , Lei Gao 1, * , Zhenting Zhou 1 , Haiyan Lin 1 , Chun Chen 3 , Peng Huang 1 , Weiliang Huang 1 , Chuying Zhou 1 , Shaohui Huang 1 , Linghui Nie 1 , Ye Liu 4 , Youming Chen 4 , Daqiao Zhou 2 and Zhiping Lv 1 1 School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China 2 Department of Liver Diseases, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong, 518033, China 3 Department of Pharmacology, Shantou University Medical College, Shantou, Guangdong, 515041, China 4 The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, 510630, China * These authors contributed equally to this work Correspondence to: Zhiping Lv, email: lzp48241@126.com Daqiao Zhou, email: zdqdoctor@sina.com 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 ABSTRACT 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.