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: Yuhei Shibata, Takeshi Hara, Junji Nagano, Nobuhiko Nakamura, Tomohiko Ohno, Soranobu Ninomiya, Hiroyasu Ito, Takuji Tanaka, Kuniaki Saito, Mitsuru Seishima, Masahito Shimizu, Hisataka Moriwaki, Hisashi Tsurumi
• Journal: PloS one (PLoS One) Vol. 11 Issue 1 Pg. e0146279 ( 2016) ISSN: 1932-6203 [Electronic] United States
• PMID: 26727596 (Publication Type: Journal Article)

Chemical References

• CD8 Antigens
• Forkhead Transcription Factors
• Foxp3 protein, mouse
• IDO1 protein, mouse
• Indoleamine-Pyrrole 2,3,-Dioxygenase
• Neoplasm Proteins
• Pore Forming Cytotoxic Proteins
• Tumor Necrosis Factor-alpha
• perforin, mouse
• Kynurenine
• Diethylnitrosamine
• Interferon-gamma
• Ptgs2 protein, mouse
• Cyclooxygenase 2
• Granzymes
• Gzmb protein, mouse

Topics

• Adenoma (chemically induced, enzymology, immunology)
• Animals
• CD8 Antigens (biosynthesis, genetics)
• Cyclooxygenase 2 (biosynthesis, genetics)
• Diethylnitrosamine
• Disease Progression
• Forkhead Transcription Factors (biosynthesis, genetics)
• Gene Expression Regulation, Neoplastic
• Granzymes (biosynthesis, genetics)
• Immune Tolerance
• Indoleamine-Pyrrole 2,3,-Dioxygenase (deficiency, genetics, physiology)
• Interferon-gamma (biosynthesis, genetics)
• Kynurenine (biosynthesis, physiology)
• Liver Neoplasms, Experimental (chemically induced, enzymology, immunology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Neoplasm Proteins (genetics, physiology)
• Pore Forming Cytotoxic Proteins (biosynthesis, genetics)
• Precancerous Conditions (chemically induced, enzymology)
• T-Lymphocytes, Cytotoxic (immunology)
• T-Lymphocytes, Regulatory (immunology)
• Tumor Necrosis Factor-alpha (biosynthesis, genetics)