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

30 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
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Immunology

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