IDO1 plays an immunosuppressive role in 2,4,6-Trinitrobenzene sulfate-induced colitis in mice

Manabu Takamatsu, Akihiro Hirata, Hirofumi Ohtaki, Masato Hoshi, Yuichiro Hatano, Hiroyuki Tomita, Toshiya Kuno, Kuniaki Saito, Akira Hara

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

IDO, an enzyme that degrades the essential amino acid L-tryptophan to N-formylkynurenine, is known to exert immunomodulatory effects in a number of diseases and disorders. IDO expression is increased in tumors, where it is thought to be involved in tumor evasion by suppressing the immune response. A competitive inhibitor of IDO is currently being tested in clinical trials for relapsed or refractory solid tumors; however, there remains a concern that attenuation of the immunosuppressive function of IDO might exacerbate inflammatory responses. In this study, we investigated the role of IDO in 2,4,6-trinitrobenzene sulfate (TNBS)-induced colitis in mice by gene deletion and pharmacological inhibition. TNBS treatment induced significantly more severe colitis in Ido1 gene-deficient (Ido1-/-) mice than in Ido1 wild-type (Ido1+/+) mice, indicating a role for IDO1 in suppression of acute colitis. Consistent with this, the expression of Ido1 was increased in the colonic interstitial tissues of TNBS-treated Ido1+/+ mice. Furthermore, transplantation of Ido1+/+ bone marrow cells into Ido1-/- mice reduced the pathological damage associated with colitis, altered the expression of cytokines, including IFN-γ, TNF-α, and IL-10, and increased the number of CD4+ Foxp3+ regulatory T cells in the colon. Pharmacological inhibition of IDO enzymatic activity by oral administration of 1-methyltryptophan (1-methyl-L-tryptophan or 1-methyl-D-tryptophan) significantly increased the severity of TNBS-induced colitis in mice, demonstrating that both stereoisomers can promote colitis. Collectively, our data indicate that IDO1 plays an important immunoregulatory role in the colon.

Original languageEnglish
Pages (from-to)3057-3064
Number of pages8
JournalJournal of Immunology
Volume191
Issue number6
DOIs
Publication statusPublished - 15-09-2013

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Colitis
Immunosuppressive Agents
Sulfates
Trinitrobenzenes
Tryptophan
Colon
Pharmacology
Tumor Escape
Stereoisomerism
Essential Amino Acids
Gene Deletion
Regulatory T-Lymphocytes
Bone Marrow Transplantation
Interleukin-10
Genes
Oral Administration
sym-trinitrobenzene
Neoplasms
Clinical Trials
Cytokines

All Science Journal Classification (ASJC) codes

  • Immunology

Cite this

Takamatsu, Manabu ; Hirata, Akihiro ; Ohtaki, Hirofumi ; Hoshi, Masato ; Hatano, Yuichiro ; Tomita, Hiroyuki ; Kuno, Toshiya ; Saito, Kuniaki ; Hara, Akira. / IDO1 plays an immunosuppressive role in 2,4,6-Trinitrobenzene sulfate-induced colitis in mice. In: Journal of Immunology. 2013 ; Vol. 191, No. 6. pp. 3057-3064.
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abstract = "IDO, an enzyme that degrades the essential amino acid L-tryptophan to N-formylkynurenine, is known to exert immunomodulatory effects in a number of diseases and disorders. IDO expression is increased in tumors, where it is thought to be involved in tumor evasion by suppressing the immune response. A competitive inhibitor of IDO is currently being tested in clinical trials for relapsed or refractory solid tumors; however, there remains a concern that attenuation of the immunosuppressive function of IDO might exacerbate inflammatory responses. In this study, we investigated the role of IDO in 2,4,6-trinitrobenzene sulfate (TNBS)-induced colitis in mice by gene deletion and pharmacological inhibition. TNBS treatment induced significantly more severe colitis in Ido1 gene-deficient (Ido1-/-) mice than in Ido1 wild-type (Ido1+/+) mice, indicating a role for IDO1 in suppression of acute colitis. Consistent with this, the expression of Ido1 was increased in the colonic interstitial tissues of TNBS-treated Ido1+/+ mice. Furthermore, transplantation of Ido1+/+ bone marrow cells into Ido1-/- mice reduced the pathological damage associated with colitis, altered the expression of cytokines, including IFN-γ, TNF-α, and IL-10, and increased the number of CD4+ Foxp3+ regulatory T cells in the colon. Pharmacological inhibition of IDO enzymatic activity by oral administration of 1-methyltryptophan (1-methyl-L-tryptophan or 1-methyl-D-tryptophan) significantly increased the severity of TNBS-induced colitis in mice, demonstrating that both stereoisomers can promote colitis. Collectively, our data indicate that IDO1 plays an important immunoregulatory role in the colon.",
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Takamatsu, M, Hirata, A, Ohtaki, H, Hoshi, M, Hatano, Y, Tomita, H, Kuno, T, Saito, K & Hara, A 2013, 'IDO1 plays an immunosuppressive role in 2,4,6-Trinitrobenzene sulfate-induced colitis in mice', Journal of Immunology, vol. 191, no. 6, pp. 3057-3064. https://doi.org/10.4049/jimmunol.1203306

IDO1 plays an immunosuppressive role in 2,4,6-Trinitrobenzene sulfate-induced colitis in mice. / Takamatsu, Manabu; Hirata, Akihiro; Ohtaki, Hirofumi; Hoshi, Masato; Hatano, Yuichiro; Tomita, Hiroyuki; Kuno, Toshiya; Saito, Kuniaki; Hara, Akira.

In: Journal of Immunology, Vol. 191, No. 6, 15.09.2013, p. 3057-3064.

Research output: Contribution to journalArticle

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T1 - IDO1 plays an immunosuppressive role in 2,4,6-Trinitrobenzene sulfate-induced colitis in mice

AU - Takamatsu, Manabu

AU - Hirata, Akihiro

AU - Ohtaki, Hirofumi

AU - Hoshi, Masato

AU - Hatano, Yuichiro

AU - Tomita, Hiroyuki

AU - Kuno, Toshiya

AU - Saito, Kuniaki

AU - Hara, Akira

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Y1 - 2013/9/15

N2 - IDO, an enzyme that degrades the essential amino acid L-tryptophan to N-formylkynurenine, is known to exert immunomodulatory effects in a number of diseases and disorders. IDO expression is increased in tumors, where it is thought to be involved in tumor evasion by suppressing the immune response. A competitive inhibitor of IDO is currently being tested in clinical trials for relapsed or refractory solid tumors; however, there remains a concern that attenuation of the immunosuppressive function of IDO might exacerbate inflammatory responses. In this study, we investigated the role of IDO in 2,4,6-trinitrobenzene sulfate (TNBS)-induced colitis in mice by gene deletion and pharmacological inhibition. TNBS treatment induced significantly more severe colitis in Ido1 gene-deficient (Ido1-/-) mice than in Ido1 wild-type (Ido1+/+) mice, indicating a role for IDO1 in suppression of acute colitis. Consistent with this, the expression of Ido1 was increased in the colonic interstitial tissues of TNBS-treated Ido1+/+ mice. Furthermore, transplantation of Ido1+/+ bone marrow cells into Ido1-/- mice reduced the pathological damage associated with colitis, altered the expression of cytokines, including IFN-γ, TNF-α, and IL-10, and increased the number of CD4+ Foxp3+ regulatory T cells in the colon. Pharmacological inhibition of IDO enzymatic activity by oral administration of 1-methyltryptophan (1-methyl-L-tryptophan or 1-methyl-D-tryptophan) significantly increased the severity of TNBS-induced colitis in mice, demonstrating that both stereoisomers can promote colitis. Collectively, our data indicate that IDO1 plays an important immunoregulatory role in the colon.

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