Expression of indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase in early concepti

Suzuki, Sachiko; Toné, Shigenobu; Takikawa, Osamu; Kubo, Toshikazu; Kohno, Ichiro; Minatogawa, Yohsuke

doi:10.1042/bj3550425

Cited by 82 publications

(63 citation statements)

References 13 publications

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“…It has been reported that IDO expression peaks at around day 10 of pregnancy and falls until it is barely detectable at day 18 (25). To confirm this in our mouse strain, Northern blots of total RNA isolated on days 9, 10, 12, 14, 15, 16, and 17 of pregnancy in ϩ/Csf1 op females were probed with a radiolabeled IDO cDNA (Fig.…”

Section: Placental Ido Expression During Normal Pregnancysupporting

confidence: 67%

“…Tissues were subsequently processed for paraffin sectioning. Five-micrometer sections were immunostained with rabbit anti-mouse IDO antiserum (1/400 dilution; 1 h at room temperature) (25) and developed using a peroxidase detection kit (Vector Laboratories, Burlingame, CA). The IDO immunohistochemistry protocol was kindly provided by Dr. N. Hunt (Department of Pathology, University of Sydney, New South Wales, Australia).…”

Section: Immunohistochemistrymentioning

confidence: 99%

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Indoleamine 2,3-Dioxygenase Is Regulated by IFN-γ in the Mouse Placenta DuringListeria monocytogenesInfection

Mackler¹,

Barber²,

Takikawa

et al. 2003

The Journal of Immunology

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The tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) is expressed in macrophages that have been differentiated in the presence of CSF-1 and is important in the containment of intracellular pathogens. IDO also appears to play a role in suppression of T cell responses in a variety of contexts. In the placenta, its enzymatic activity is believed to establish a chemical barrier that protects the fetal allograft from T cell-mediated immune aggression. We have studied the regulation of IDO in the utero-placental unit of mice following infection with the Gram-positive, intracellular bacterium Listeria monocytogenes that has a predilection for replication in the decidua basalis. IDO mRNA and protein expression is enhanced in the utero-placental unit following infection with L. monocytogenes. However, in contrast to the human where IDO is expressed by the CSF-1R-positive syncytial trophoblast, IDO is not expressed in murine trophoblastic tissue but instead is found in stromal cells of the decidua basalis and metrial gland and following infection, in endothelial cells. Using mice carrying null mutations in cytokine/growth factor genes, we explored the regulation of IDO in the placenta. Consistent with the absence of CSF-1R expression in the IDO-expressing cells of mice, neither the basal levels of IDO nor its induction following infection is affected by the absence of CSF-1. However, although the basal level of IDO is normal, the enhanced expression during Listeriosis is completely abrogated in the absence of IFN-γ, a cytokine required for the resolution of this infection. These data suggest that IDO plays a role in resolving bacterial infection in the placenta while at the same time maintaining a barrier to T cells whose presence might result in fetal rejection.

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Section: Placental Ido Expression During Normal Pregnancysupporting

confidence: 67%

Section: Immunohistochemistrymentioning

confidence: 99%

Indoleamine 2,3-Dioxygenase Is Regulated by IFN-γ in the Mouse Placenta DuringListeria monocytogenesInfection

Mackler¹,

Barber²,

Takikawa

et al. 2003

The Journal of Immunology

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“…Interestingly, the immunosuppressive effect of liver-expressed TDO might contribute to the allograft tolerance usually observed after liver transplantation, as recently suggested (9). Similarly, low levels of TDO were observed in early concepti, where they might contribute to tolerance of the embryo by the maternal immune system (31)(32)(33).…”

Section: Discussionmentioning

confidence: 95%

Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase

Pilotte

Larrieu

Stroobant

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

512

532

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Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase (IDO1) is an important mechanism of peripheral immune tolerance contributing to tumoral immune resistance, and IDO1 inhibition is an active area of drug development. Tryptophan 2,3-dioxygenase (TDO) is an unrelated hepatic enzyme that also degrades tryptophan along the kynurenine pathway. Here, we show that enzymatically active TDO is expressed in a significant proportion of human tumors. In a preclinical model, TDO expression by tumors prevented their rejection by immunized mice. We developed a TDO inhibitor, which, upon systemic treatment, restored the ability of mice to reject TDO-expressing tumors. Our results describe a mechanism of tumoral immune resistance based on TDO expression and establish proof-of-concept for the use of TDO inhibitors in cancer therapy.T ryptophan 2,3-dioxygenase (TDO) is a homotetrameric hemecontaining cytosolic enzyme encoded by gene TDO2 and expressed at high levels in the liver. It catalyses the first and ratelimiting step of tryptophan degradation along the kynurenine pathway and thereby regulates systemic tryptophan levels. The same reaction can be catalyzed by another heme-containing cytosolic enzyme, named indoleamine 2,3-dioxygenase (IDO1), which has no sequence similarity with TDO, is not expressed in the liver, and is monomeric. IDO1 has been the focus of attention in recent years because of its immunosuppressive effects on T lymphocytes, resulting partly from tryptophan depletion and partly from direct effects of tryptophan catabolites (1-3). IDO1 is expressed constitutively in the placenta, where it plays a key role in feto-maternal tolerance (2), and in many tumors, where it contributes to tumoral resistance to immune rejection (4-7). IDO1 expression is also inducible in many cells, including dendritic cells, and appears to play a role in peripheral immune tolerance and the retro-control of immune responses (8). In contrast, little is known about the effect of TDO expression on the immune response. A recent report indicated that human cells transfected with TDO depleted tryptophan and thereby prevented both the growth of pathogens and the proliferation of allogeneic T lymphocytes (9). These results suggested that TDO might mediate immunosuppressive effects similar to those of IDO1. We set out to examine whether tumor cells express TDO and thereby inhibit T-cell-mediated immune responses. ResultsWe first observed that many human tumor samples expressed gene TDO2 as measured by real-time RT-PCR (Table 1). This was the case for 41% of bladder carcinomas, 50% of melanomas and 100% of hepatocarcinomas. To confirm the activity of TDO in tumor cells, we selected a series of human tumor cell lines that also expressed the TDO2 mRNA. We incubated cells for 24 h in medium containing a known concentration of tryptophan, and measured by HPLC in the supernatant the concentration of tryptophan and kynurenine, which is the main tryptophan catabolite (Table 2). HEK-293 cells transfected or not with human TDO2 were used as pos...

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“…The total RNA (10 mg per lane) was electrophoresed in a formaldehyde gel (1.2% agarose), blotted on to nylon membranes (Hybond N, Amersham) and then probed with radiolabelled IDO cDNA fragments as described previously (Suzuki et al 2001). In the case of the IDO Northern-blot analysis, the probe was made by RT-PCR (5 0 primer, 5 0 -AGGATCCTTGA-AGACCACCA-3 0 ; 3 0 primer, 5 0 -CCAATAGAGAG-ACGAGGAAG-3 0 , obtained from GenBank, accession no.…”

Section: Northern-blot Analysis Of Idomentioning

confidence: 99%

“…The serum containing the anti-mouse IDO polyclonal antibody was obtained from rabbits that were immunized with a mixture of three peptides corresponding to amino acids 1-18, 156-175 and 359-377 of mouse IDO protein (Suzuki et al 2001).…”

Section: Polyclonal Antibodymentioning

confidence: 99%

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

et al. 2007

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Indoleamine 2,3-dioxygenase (IDO; EC 1.13.11.42) is a rate-limiting enzyme involved in the catabolism of tryptophan, which is an essential amino acid. It is induced under pathological conditions, such as the presence of viral infections or tumour cells. This enzyme is induced by IFN-c in the mouse rectal carcinoma cell line CMT-93. It is known that both 1-methyl-L-tryptophan (1-MT) and methylthiohydantoin-DL-tryptophan (MTH-trp) are tryptophan analogues, and are authentic inhibitors of the enzymatic activity of IDO. In this study, we examined the effects of both 1-MT and MTH-trp on the IFN-c inducible IDO expression of CMT-93. As a result, the IFN-c inducible IDO mRNA and the protein levels in CMT-93 were suppressed by 1-MT and MTH-trp, independently. Moreover, tryptophan (Trp), as a substrate of IDO, also suppressed IDO induction by IFN-c at the transcriptional level. These results suggest that 1-MT and MTH-trp are as inhibitors of IDO enzymatic activity, and Trp suppresses IDO induction by IFN-c at the transcriptional level.

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Expression of indoleamine 2,3-dioxygenase and tryptophan 2,3-dioxygenase in early concepti

Cited by 82 publications

References 13 publications

Indoleamine 2,3-Dioxygenase Is Regulated by IFN-γ in the Mouse Placenta DuringListeria monocytogenesInfection

Indoleamine 2,3-Dioxygenase Is Regulated by IFN-γ in the Mouse Placenta DuringListeria monocytogenesInfection

Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase

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

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