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

نویسندگان

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

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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عنوان ژورنال:
  • Journal of immunology

دوره 191 6  شماره 

صفحات  -

تاریخ انتشار 2013