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Emerging Roles on Immunological Effect of Indoleamine 2,3-Dioxygenase in Liver Injuries.

ABSTRACT: Indoleamine 2,3-dioxygenase (IDO) is one of the initial rate-limiting enzymes of the kynurenine pathway (KP), which causes immune suppression and induction of T cell anergy. It is associated with the imbalance of immune homeostasis in numerous diseases including cancer, chronic viral infection, allergy, and autoimmune diseases. Recently, IDO has extended its role to liver field. In this review, we summarize the dysregulation and potentials of IDO in the emerging field of liver injuries, as well as current challenges for IDO targets. In particular, we discuss unexpected conclusions against previous work published. IDO is induced by pro-inflammatory cytokines in liver dysfunction and exerts an immunosuppressive effect, whereas the improvement of liver injury may require consideration of multiple factors besides IDO.

SUBMITTER: Xu L

PROVIDER: S-EPMC8636938 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Emerging Roles on Immunological Effect of Indoleamine 2,3-Dioxygenase in Liver Injuries.

Xu Lingyan L Ling Jiawei J Su Chang C Su Yu-Wen YW Xu Yan Y Jiang Zhenzhou Z

Frontiers in medicine 20211118

Indoleamine 2,3-dioxygenase (IDO) is one of the initial rate-limiting enzymes of the kynurenine pathway (KP), which causes immune suppression and induction of T cell anergy. It is associated with the imbalance of immune homeostasis in numerous diseases including cancer, chronic viral infection, allergy, and autoimmune diseases. Recently, IDO has extended its role to liver field. In this review, we summarize the dysregulation and potentials of IDO in the emerging field of liver injuries, as well ...[more]

PMID: 34869457

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A narrative review of the roles of indoleamine 2,3-dioxygenase and tryptophan-2,3-dioxygenase in liver diseases.

Project description:Indoleamine 2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO) are induced by several immune factors, such as interferon-γ, and act as intracellular enzymes that catabolize essential amino acid tryptophan into kynurenine and other downstream metabolites, including kynurenic acid (KYNA), xanthurenic acid (XA) and so on. IDO and TDO work as a double-edge sword. On one hand, they exert the immunomodulatory effects, especially immunosuppressive effects on the microenvironment including infections, pregnancy, tumor cells escape and transplantation. TDO plays the major role under basal conditions, while IDO comes into play under different circumstances of immune activation, thus IDO has a wider spectrum of immune regulation. On the other hand, these enzymes also inhibit pathogens such as Chlamydia pneumoniae, Staphylococcus aureus, Toxoplasma gondii and so on. Moreover, IDO regulates metabolic health through shaping intestinal microbiota. Recently, these enzymes have attracted more and more attention in liver diseases. Several studies have indicated that IDO and TDO can modulate viral hepatitis, autoimmune liver diseases, non-alcoholic fatty liver disease (NAFLD), liver cirrhosis, liver cancer even liver transplantation. Targeting them or their antagonists may provide novel therapeutic treatments for liver diseases. In this review, we will discuss the exact roles that IDO and TDO play in diverse hepatic diseases.

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| S-EPMC1221754 | biostudies-other

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Project description:The first and rate-limiting step of the kynurenine pathway, in which tryptophan (Trp) is converted to N-formylkynurenine is catalyzed by two heme-containing proteins, Indoleamine 2,3-dioxygenase (IDO), and Tryptophan 2,3-dioxygenase (TDO). In mammals, TDO is found exclusively in liver tissue, IDO is found ubiquitously in all tissues. IDO has become increasingly popular in pharmaceutical research as it was found to be involved in many physiological situations, including immune escape of cancer. More importantly, small-molecule inhibitors of IDO are currently utilized in cancer therapy. One of the main concerns for the design of human IDO (hIDO) inhibitors is that they should be selective enough to avoid inhibition of TDO. In this work, we have used a combination of classical molecular dynamics (MD) and hybrid quantum-classical (QM/MM) methodologies to establish the structural basis that determine the differences in (a) the interactions of TDO and IDO with small ligands (CO/O(2)) and (b) the substrate stereo-specificity in hIDO and TDO. Our results indicate that the differences in small ligand bound structures of IDO and TDO arise from slight differences in the structure of the bound substrate complex. The results also show that substrate stereo-specificity of TDO is achieved by the perfect fit of L-Trp, but not D-Trp, which exhibits weaker interactions with the protein matrix. For hIDO, the presence of multiple stable binding conformations for L/D-Trp reveal the existence of a large and dynamic active site. Taken together, our data allow determination of key interactions useful for the future design of more potent hIDO-selective inhibitors.

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NADH oxidase activity of indoleamine 2,3-dioxygenase.

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Indole peroxygenase activity of indoleamine 2,3-dioxygenase.

Project description:The heme enzyme indoleamine 2,3-dioxygenase (IDO) was found to catalyze the oxidation of indole by H(2)O(2), with generation of 2- and 3-oxoindole as the major products. This reaction occurred in the absence of O(2) and reducing agents and was not inhibited by superoxide dismutase or hydroxyl radical scavengers, although it was strongly inhibited by L-Trp. The stoichiometry of the reaction indicated a one-to-one correspondence for the consumption of indole and H(2)O(2). The (18)O-labeling experiments indicated that the oxygen incorporated into the monooxygenated products was derived almost exclusively from H(2)(18)O(2), suggesting that electron transfer was coupled to the transfer of oxygen from a ferryl intermediate of IDO. These results demonstrate that IDO oxidizes indole by means of a previously unrecognized peroxygenase activity. We conclude that IDO inserts oxygen into indole in a reaction that is mechanistically analogous to the "peroxide shunt" pathway of cytochrome P450.

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