Effects of indoleamine 2,3-dioxygenase inhibitor in non-Hodgkin lymphoma model mice

Nakamura, Nobuhiko; Hara, Takeshi; Shimizu, Masahito; Mabuchi, Ryoko; Nagano, Junko; Ohno, Tomohiro; Kochi, Takeshi; Kubota, Minoru; Shirakami, Yohei; Goto, Naoe; Ito, Hiroyasu; Tanaka, Takuji; Moriwaki, Hisataka; Tsurumi, Hisashi

doi:10.1007/s12185-015-1835-8

Cited by 21 publications

(17 citation statements)

References 40 publications

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“…Reduction of the kynurenine levels in the microenvironment by using IDO inhibitors impedes the growth of IDO-expressing tumors [ 53 ]. In addition, up-regulation of IDO is possibly involved in lymphoma or colon carcinogenesis, whereas treatment with 1-MT, an IDO inhibitor, effectively suppresses chemically induced lymphoma or colorectal carcinogenesis by inhibiting IDO activity [ 22 , 23 ]. ( − )-Epigallocatechin gallate, one of the green tea catechins that can decrease IFN-γ-induced IDO expression in colon cancer cells [ 54 ], also suppresses colorectal carcinogenesis through the inhibition of IDO activity and COX-2 expression [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, several preclinical studies have demonstrated that IDO inhibitors, such as 1-methyl-tryptophan (1-MT), are therapeutically beneficial for inhibition of cancer cell growth, especially when they are combined with different types of cytotoxic chemotherapeutic agents [ 20 , 21 ]. We have also reported that IDO up-regulation accelerates chemically induced colorectal carcinogenesis in rats, whereas supplementation with 1-MT suppresses this carcinogenesis by inhibiting the expression and activation of IDO [ 22 , 23 ]. These reports suggest that targeting IDO might be an effective strategy for the treatment and the prevention of certain types of human malignancies.…”

Section: Introductionmentioning

confidence: 99%

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The Role of Indoleamine 2,3-Dioxygenase in Diethylnitrosamine-Induced Liver Carcinogenesis

et al. 2016

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Indoleamine 2,3-dioxygenase (IDO), a tryptophan-catabolizing intracellular enzyme of the L-kynurenine pathway, causes preneoplastic cells and tumor cells to escape the immune system by inducing immune tolerance; this mechanism might be associated with the development and progression of human malignancies. In the present study, we investigated the role of IDO in diethylnitrosamine (DEN)-induced hepatocarcinogenesis by using IDO-knockout (KO) mice. To induce hepatocellular carcinoma (HCC), hepatic adenoma, and preneoplastic hepatocellular lesions termed foci of cellular alteration (FCA), male IDO-wild-type (WT) and IDO-KO mice with a C57BL/6J background received a single intraperitoneal injection of DEN at 2 weeks of age. The mice were sacrificed to evaluate the development of FCA and hepatocellular neoplasms. HCC overexpressed IDO and L-kynurenine compared to surrounding normal tissue in the DEN-treated IDO-WT mice. The number and cell proliferative activity of FCAs, and the incidence and multiplicity of HCC were significantly greater in the IDO-WT than in the IDO-KO mice. The expression levels of the IDO protein, of L-kynurenine, and of IFN-γ, COX-2, TNF-α, and Foxp3 mRNA were also significantly increased in the DEN-induced hepatic tumors that developed in the IDO-WT mice. The mRNA expression levels of CD8, perforin and granzyme B were markedly increased in hepatic tumors developed in IDO-KO mice. Moreover, Foxp3-positive inflammatory cells had infiltrated into the livers of DEN-treated IDO-WT mice, whereas fewer cells had infiltrated into the livers of IDO-KO mice. Induction of IDO and elevation of L-kynurenine might play a critical role in both the early and late phase of liver carcinogenesis. Our findings suggest that inhibition of IDO might offer a promising strategy for the prevention of liver cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The Role of Indoleamine 2,3-Dioxygenase in Diethylnitrosamine-Induced Liver Carcinogenesis

et al. 2016

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“…A subset of WT mice received daily 1- D -MT (Sigma, USA) dissolved in drinking water (5 mg/ml, pH 10.7) [41, 42]. Mice were maintained in pathogen-free facilities at Southern Medical University.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2017

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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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“…Moreover, the objective of our in vitro studies was to determine whether and which enzymes of the kynurenine pathway are derived from microglia cells. Finally, we posed a question whether the inhibitors of two enzymes (selected on the basis of biochemical studies) of the kynurenine pathway influence hypersensitivity in a rat model of neuropathic pain – UPF 648, a KMO inhibitor ( Pellicciari et al, 2003 ) and 1- D -MT, an IDO inhibitor ( Nakamura et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Pharmacological Inhibition of Indoleamine 2,3-Dioxygenase-2 and Kynurenine 3-Monooxygenase, Enzymes of the Kynurenine Pathway, Significantly Diminishes Neuropathic Pain in a Rat Model

et al. 2018

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Neuropathic pain caused by a primary injury or dysfunction in the peripheral or central nervous system is a tremendous therapeutic challenge. Here, we have collected the first evidence from a single study on the potential contributions to neuropathic pain development by enzymes in the kynurenine pathway [tryptophan 2,3-dioxygenase (TDO), indoleamine 2,3-dioxygenase (IDO1/2), kynurenine 3-monooxygenase (KMO); kynureninase, 3-hydroxyanthranilate-3,4-dioxygenase (HAOO)] at the spinal cord and dorsal root ganglia (DRG) levels. At the spinal cord, mRNA levels of IDO2, KMO, and HAOO were elevated as measured on day 7 after chronic constriction injury in a rat model, parallel to the C1q-positive cell activation. According to our data obtained from primary microglial cell cultures, all enzymes of the kynurenine pathway except TDO were derived from these cells; however, the activation of microglia induced stronger changes in IDO2 and KMO. Our pharmacological studies gave evidence that the repeated intraperitoneal administration of minocycline, a microglia/macrophage inhibitor, not only attenuated tactile and thermal hypersensitivity but also diminished the levels of IDO2 and KMO mRNA. Our further pharmacological studies confirmed that IDO2 and KMO enzymes take part in the development of neuropathic pain, since we observed that the repeated administration of IDO2 (1-methyl-D-tryptophan) and KMO [UPF 648 – (1S,2S)-2-(3,4-dichlorobenzoyl)cyclopropanecarboxylic acid] inhibitors diminished hypersensitivity development as measured on days 2 and 7. The results of our studies show that the kynurenine pathway is an important mediator of neuropathic pain pathology in rats and indicate that IDO2 and KMO represent novel pharmacological targets for treating neuropathy.

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Effects of indoleamine 2,3-dioxygenase inhibitor in non-Hodgkin lymphoma model mice

Cited by 21 publications

References 40 publications

The Role of Indoleamine 2,3-Dioxygenase in Diethylnitrosamine-Induced Liver Carcinogenesis

The Role of Indoleamine 2,3-Dioxygenase in Diethylnitrosamine-Induced Liver Carcinogenesis

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

Pharmacological Inhibition of Indoleamine 2,3-Dioxygenase-2 and Kynurenine 3-Monooxygenase, Enzymes of the Kynurenine Pathway, Significantly Diminishes Neuropathic Pain in a Rat Model

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