The role of indoleamine 2,3-dioxygenase in diethylnitrosamine-induced liver carcinogenesis

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

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish
Article numbere0146279
JournalPloS one
Volume11
Issue number1
DOIs
Publication statusPublished - 04-01-2016

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Indoleamine-Pyrrole 2,3,-Dioxygenase
Diethylnitrosamine
Liver
carcinogenesis
Carcinogenesis
liver
Kynurenine
mice
Knockout Mice
kynurenine
liver neoplasms
hepatoma
Tumors
Hepatocellular Carcinoma
diethylnitrosamine
indoleamine 2,3-dioxygenase
Neoplasms
Liver Cell Adenoma
cells
Immune Tolerance

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Shibata, Y., Hara, T., Nagano, J., Nakamura, N., Ohno, T., Ninomiya, S., ... Tsurumi, H. (2016). The role of indoleamine 2,3-dioxygenase in diethylnitrosamine-induced liver carcinogenesis. PloS one, 11(1), [e0146279]. https://doi.org/10.1371/journal.pone.0146279
Shibata, Yuhei ; Hara, Takeshi ; Nagano, Junji ; Nakamura, Nobuhiko ; Ohno, Tomohiko ; Ninomiya, Soranobu ; Ito, Hiroyasu ; Tanaka, Takuji ; Saito, Kuniaki ; Seishima, Mitsuru ; Shimizu, Masahito ; Moriwaki, Hisataka ; Tsurumi, Hisashi. / The role of indoleamine 2,3-dioxygenase in diethylnitrosamine-induced liver carcinogenesis. In: PloS one. 2016 ; Vol. 11, No. 1.
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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.",
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Shibata, Y, Hara, T, Nagano, J, Nakamura, N, Ohno, T, Ninomiya, S, Ito, H, Tanaka, T, Saito, K, Seishima, M, Shimizu, M, Moriwaki, H & Tsurumi, H 2016, 'The role of indoleamine 2,3-dioxygenase in diethylnitrosamine-induced liver carcinogenesis', PloS one, vol. 11, no. 1, e0146279. https://doi.org/10.1371/journal.pone.0146279

The role of indoleamine 2,3-dioxygenase in diethylnitrosamine-induced liver carcinogenesis. / Shibata, Yuhei; Hara, Takeshi; Nagano, Junji; Nakamura, Nobuhiko; Ohno, Tomohiko; Ninomiya, Soranobu; Ito, Hiroyasu; Tanaka, Takuji; Saito, Kuniaki; Seishima, Mitsuru; Shimizu, Masahito; Moriwaki, Hisataka; Tsurumi, Hisashi.

In: PloS one, Vol. 11, No. 1, e0146279, 04.01.2016.

Research output: Contribution to journalArticle

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T1 - The role of indoleamine 2,3-dioxygenase in diethylnitrosamine-induced liver carcinogenesis

AU - Shibata, Yuhei

AU - Hara, Takeshi

AU - Nagano, Junji

AU - Nakamura, Nobuhiko

AU - Ohno, Tomohiko

AU - Ninomiya, Soranobu

AU - Ito, Hiroyasu

AU - Tanaka, Takuji

AU - Saito, Kuniaki

AU - Seishima, Mitsuru

AU - Shimizu, Masahito

AU - Moriwaki, Hisataka

AU - Tsurumi, Hisashi

PY - 2016/1/4

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N2 - 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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Shibata Y, Hara T, Nagano J, Nakamura N, Ohno T, Ninomiya S et al. The role of indoleamine 2,3-dioxygenase in diethylnitrosamine-induced liver carcinogenesis. PloS one. 2016 Jan 4;11(1). e0146279. https://doi.org/10.1371/journal.pone.0146279