title: IDO1 plays an immunosuppressive role in 2,4,6-trinitrobenzene sulfate-induced colitis in mice.
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.
authors: Department of Tumor Pathology, Gifu University Graduate School of Medicine, Yanagido 1-1, Gifu 501-1194, Japan.
authors: Manabu
authors: M
authors: Takamatsu
authors: Akihiro
authors: A
authors: Hirata
authors: Hirofumi
authors: H
authors: Ohtaki
authors: Masato
authors: M
authors: Hoshi
authors: Yuichiro
authors: Y
authors: Hatano
authors: Hiroyuki
authors: H
authors: Tomita
authors: Toshiya
authors: T
authors: Kuno
authors: Kuniaki
authors: K
authors: Saito
authors: Akira
authors: A
authors: Hara
mesh_terms: D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000201:enzymology* / Q000276:immunology; D004195:Disease Models, Animal; D007108:Immune Tolerance / Q000276:immunology*; D007150:Immunohistochemistry; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D014301:Trinitrobenzenes / Q000633:toxicity
chemical_list: C583637:IDO1 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D014301:Trinitrobenzenes