Transcriptional regulation of indoleamine 2,3-dioxygenase (IDO) by tryptophan and its analogue

Okamoto, Takeaki; Toné, Shigenobu; Kanouchi, Hiroaki; Miyawaki, Chie; Ono, Sayuri; Minatogawa, Yohsuke

doi:10.1007/s10616-007-9081-4

Cited by 27 publications

(9 citation statements)

References 19 publications

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“…Previous studies in rodents and in cell cultures showed that 1-MT (L-isomer) reduced the production of metabolites in the KYN pathway and prevented the depletion of TRP [ 3 , 13 , 28 , 29 ]. In studies using a recombinant IDO1 enzyme in cell-free assay systems, the L-isomer of 1-MT (K i = 19 μM/L) was found to be a more potent inhibitor of IDO1 than the D-isomer (K i > 100 μM/L) [ 13 ].…”

Section: Discussionmentioning

confidence: 99%

Effects of 1-Methyltryptophan on Immune Responses and the Kynurenine Pathway after Lipopolysaccharide Challenge in Pigs

Wirthgen

Otten

Tuchscherer

et al. 2018

IJMS

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An enhanced indoleamine 2,3-dioxygenase 1 (IDO1) activity is associated with an increased mortality risk in sepsis patients. Thus, the preventive inhibition of IDO1 activity may be a promising strategy to attenuate the severity of septic shock. 1-methyltryptophan (1-MT) is currently in the interest of research due to its potential inhibitory effects on IDO1 and immunomodulatory properties. The present study aims to investigate the protective and immunomodulatory effects of 1-methyltryptophan against endotoxin-induced shock in a porcine in vivo model. Effects of 1-MT were determined on lipopolysaccharide (LPS)-induced tryptophan (TRP) degradation, immune response and sickness behaviour. 1-MT increased TRP and its metabolite kynurenic acid (KYNA) in plasma and tissues, suppressed the LPS-induced maturation of neutrophils and increased inactivity of the animals. 1-MT did not inhibit the LPS-induced degradation of TRP to kynurenine (KYN)—a marker for IDO1 activity—although the increase in KYNA indicates that degradation to one branch of the KYN pathway is facilitated. In conclusion, our findings provide no evidence for IDO1 inhibition but reveal the side effects of 1-MT that may result from the proven interference of KYNA and 1-MT with aryl hydrocarbon receptor signalling. These effects should be considered for therapeutic applications of 1-MT.

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Section: Discussionmentioning

confidence: 99%

Effects of 1-Methyltryptophan on Immune Responses and the Kynurenine Pathway after Lipopolysaccharide Challenge in Pigs

Wirthgen

Otten

Tuchscherer

et al. 2018

IJMS

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“…To our knowledge this is the first report of 1-D-MT-mediated effects on gene expression in human cells. The stereoisomer of 1-D-MT, 1-L-MT was recently reported to suppress the IFN-γ-induced expression of IDO1 in mouse rectal carcinoma cells [40] . In addition, it has previously been described that 1-MT influences the maturation of DC independently of IDO [31] .…”

Section: Discussionmentioning

confidence: 99%

The Indoleamine-2,3-Dioxygenase (IDO) Inhibitor 1-Methyl-D-tryptophan Upregulates IDO1 in Human Cancer Cells

et al. 2011

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1-methyl-D-tryptophan (1-D-MT) is currently being used in clinical trials in patients with relapsed or refractory solid tumors with the aim of inhibiting indoleamine-2,3-dioxygenase (IDO)-mediated tumor immune escape. IDO is expressed in tumors and tumor-draining lymph nodes and degrades tryptophan (trp) to create an immunsuppressive micromilieu both by depleting trp and by accumulating immunosuppressive metabolites of the kynurenine (kyn) pathway. Here we show that proliferation of alloreactive T-cells cocultured with IDO1-positive human cancer cells paradoxically was inhibited by 1-D-MT. Surprisingly incubation with 1-D-MT increased kyn production of human cancer cells. Cell-free assays revealed that 1-D-MT did not alter IDO1 enzymatic activity. Instead, 1-D-MT induced IDO1 mRNA and protein expression through pathways involving p38 MAPK and JNK signalling. Treatment of cancer patients with 1-D-MT has transcriptional effects that may promote rather than suppress anti-tumor immune escape by increasing IDO1 in the cancer cells. These off-target effects should be carefully analyzed in the ongoing clinical trials with 1-D-MT.

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“…The enzymatic activity of IDO can specifically be blocked using the inhibitor 1-MT. 26 Thus, in order to further investigate the role of IDO in connection to sCD83-mediated immunosuppressive effects in our IBD model, in the following in vivo experiments IDO activity was blocked by implanting 1-MT impregnated pellets (15 mg day À 1 ) or vehicle control pellets under the dorsal skin of the neck on day À 1. DNBS was administered on day 0 and mice were treated with sCD83 on days À 1, 0, and þ 1.…”

Section: Inhibition Of Ido Interferes With Scd83-induced Protective Ementioning

confidence: 99%

Soluble CD83 ameliorates experimental colitis in mice

et al. 2014

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The physiological balance between pro- and anti-inflammatory processes is dysregulated in inflammatory bowel diseases (IBD) as in Crohn's disease and ulcerative colitis. Conventional therapy uses anti-inflammatory and immunosuppressive corticosteroids to treat acute-phase symptoms. However, low remission rate and strong side effects of these therapies are not satisfying. Thus, there is a high medical need for new therapeutic strategies. Soluble CD83, the extracellular domain of the transmembrane CD83 molecule, has been reported to have interesting therapeutic and immunosuppressive properties by suppressing dendritic cell (DC)-mediated T-cell activation and inducing tolerogenic DCs. However, the expression and function of CD83 in IBD is still unknown. Here, we show that CD83 expression is upregulated by different leukocyte populations in a chemical-induced murine colitis model. Furthermore, in this study the potential of sCD83 to modulate colitis using an experimental murine colitis model was investigated. Strikingly, sCD83 ameliorated the clinical disease symptoms, drastically reduced mortality, and strongly decreased inflammatory cytokine expression in mesenteric lymph nodes and colon. The infiltration of macrophages and granulocytes into colonic tissues was vigorously inhibited. Mechanistically, we could show that sCD83-induced expression of indolamine 2,3-dioxygenase is essential for its protective effects.

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Transcriptional regulation of indoleamine 2,3-dioxygenase (IDO) by tryptophan and its analogue

Cited by 27 publications

References 19 publications

Effects of 1-Methyltryptophan on Immune Responses and the Kynurenine Pathway after Lipopolysaccharide Challenge in Pigs

Effects of 1-Methyltryptophan on Immune Responses and the Kynurenine Pathway after Lipopolysaccharide Challenge in Pigs

The Indoleamine-2,3-Dioxygenase (IDO) Inhibitor 1-Methyl-D-tryptophan Upregulates IDO1 in Human Cancer Cells

Soluble CD83 ameliorates experimental colitis in mice

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