Journal Article

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

Seishima, Mitsuru, Shibata, Yuhei, Ninomiya, Soranobu, Tanaka, Takuji, Shimizu, Masahito, Moriwaki, Hisataka, Ohno, Tomohiko, Tsurumi, Hisashi, Ito, Hiroyasu, Hara, Takeshi, Nagano, Junji, Nakamura, Nobuhiko, Saito, Kuniaki

2016

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adenoma / Adenoma - chemically induced / Adenoma - enzymology / Adenoma - immunology / Animals / Antigens / Carcinogenesis / Carcinogens / CD8 antigen / CD8 Antigens - biosynthesis / CD8 Antigens - genetics / Cell growth / Clinical medicine / Cyclooxygenase 2 - biosynthesis / Cyclooxygenase 2 - genetics / Cyclooxygenase-2 / Development and progression / Diethylnitrosamine / Disease Progression / Enzymes / Escape systems / Forkhead Transcription Factors - biosynthesis / Forkhead Transcription Factors - genetics / Foxp3 protein / Gene expression / Gene Expression Regulation, Neoplastic / Genetic aspects / Granzyme B / Granzymes - biosynthesis / Granzymes - genetics / Health aspects / Hepatitis / Hepatocellular carcinoma / Immune response regulation / Immune system / Immune Tolerance / Immunological tolerance / Indoleamine-Pyrrole 2,3,-Dioxygenase - deficiency / Indoleamine-Pyrrole 2,3,-Dioxygenase - genetics / Indoleamine-Pyrrole 2,3,-Dioxygenase - physiology / Infections / Inflammation / Interferon / Interferon-gamma - biosynthesis / Interferon-gamma - genetics / Internal medicine / Kinases / Kynurenine - biosynthesis / Kynurenine - physiology / Lesions / Liver / Liver cancer / Liver Neoplasms, Experimental - chemically induced / Liver Neoplasms, Experimental - enzymology / Liver Neoplasms, Experimental - immunology / Lymphocytes / Male / Medical prognosis / Medicine / Mice / Mice, Inbred C57BL / Mice, Knockout / Neoplasia / Neoplasm Proteins - genetics / Neoplasm Proteins - physiology / Neoplasms / Oxidases / Perforin / Pore Forming Cytotoxic Proteins - biosynthesis / Pore Forming Cytotoxic Proteins - genetics / Precancerous Conditions - chemically induced / Precancerous Conditions - enzymology / Rodents / T-Lymphocytes, Cytotoxic - immunology / T-Lymphocytes, Regulatory - immunology / Tryptophan / Tryptophan 2,3-dioxygenase / Tumor cells / Tumor Necrosis Factor-alpha - biosynthesis / Tumor Necrosis Factor-alpha - genetics / Tumor necrosis factor-α / Tumors / University graduates / γ-Interferon