title: The Role of Indoleamine 2,3-Dioxygenase in Diethylnitrosamine-Induced Liver Carcinogenesis.
abstract: 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.
authors.affiliation: First Departments of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Yuhei
authors.initials: Y
authors.lastname: Shibata
authors.affiliation: First Departments of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hara
authors.affiliation: First Departments of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Nagano
authors.affiliation: First Departments of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Nakamura
authors.affiliation: First Departments of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Ohno
authors.affiliation: First Departments of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Soranobu
authors.initials: S
authors.lastname: Ninomiya
authors.affiliation: Departments of Informative Clinical Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Ito
authors.affiliation: Departments of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Takuji
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Human Health Sciences, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Saito
authors.affiliation: Departments of Informative Clinical Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Seishima
authors.affiliation: First Departments of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Masahito
authors.initials: M
authors.lastname: Shimizu
authors.affiliation: First Departments of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Hisataka
authors.initials: H
authors.lastname: Moriwaki
authors.affiliation: First Departments of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Tsurumi
mesh_terms: D000236:Adenoma / Q000139:chemically induced / Q000201:enzymology / Q000276:immunology; D000818:Animals; D016827:CD8 Antigens / Q000096:biosynthesis / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics; D004052:Diethylnitrosamine; D018450:Disease Progression; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D053804:Granzymes / Q000096:biosynthesis / Q000235:genetics; D007108:Immune Tolerance; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000235:genetics; D007737:Kynurenine / Q000096:biosynthesis / Q000502:physiology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000201:enzymology* / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D052899:Pore Forming Cytotoxic Proteins / Q000096:biosynthesis / Q000235:genetics; D011230:Precancerous Conditions / Q000139:chemically induced / Q000201:enzymology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics
chemical_list: D016827:CD8 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C583637:IDO1 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D009363:Neoplasm Proteins; D052899:Pore Forming Cytotoxic Proteins; D014409:Tumor Necrosis Factor-alpha; C483886:perforin, mouse; D007737:Kynurenine; D004052:Diethylnitrosamine; D007371:Interferon-gamma; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D053804:Granzymes; C509214:Gzmb protein, mouse