Tryptophan 2,3-dioxygenase is a key modulator of physiological neurogenesis and anxiety-related behavior in mice

Kanai, Masanori; Funakoshi, Hiroshi; Takahashi, Hiroyuki; Hayakawa, Tsuyoshi; Mizuno, Shinya; Matsumoto, Kunio; Nakamura, Toshikazu

doi:10.1186/1756-6606-2-8

Cited by 240 publications

(292 citation statements)

References 51 publications

Supporting

Mentioning

269

Contrasting

Order By: Relevance

“…These results confirm the effect of Tdo2 on decidualization. Because both inhibition and targeted disruption of Tdo2 could lead to an increase in available tryptophan and circulating serotonin levels (Salter et al 1995, Kanai et al 2009), Tdo2 expression in decidualized cells demonstrated that Tdo2 might increase tryptophan catabolism in the decidual zone and decrease available tryptophan for production of serotonin that could inhibit the process of decidualization (Mitchell et al 1983), which further supports a role for Tdo2 in decidualization. Tdo2 is a rate-limiting enzyme of the tryptophan degradation pathway, producing kynurenine (Thackray et al 2008).…”

Section: Discussionmentioning

confidence: 80%

“…Tdo2-deficient mice displayed an elevation of plasma tryptophan, making more of this amino acid available for uptake into the brain, where it is converted to serotonin (Kanai et al 2009). Tdo2 has also been identified in skin, brain, epididymis, testis, and early concepti, although it was mainly expressed in the liver (Suzuki et al 2001, Minatogawa et al 2003, Britan et al 2006.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Differential expression and regulation of Tdo2 during mouse decidualization

Gao

Tian

et al. 2013

Journal of Endocrinology

View full text Add to dashboard Cite

Tryptophan 2,3-dioxygenase (Tdo2) is a rate-limiting enzyme which directs the conversion of tryptophan to kynurenine. The aim of this study was to examine the expression and regulation of Tdo2 in mouse uterus during decidualization. Tdo2 mRNA was mainly expressed in the decidua on days 6-8 of pregnancy. By real-time PCR, a high level of Tdo2 expression was observed in the uteri from days 6 to 8 of pregnancy, although Tdo2 expression was observed on days 1-8. Simultaneously, Tdo2 mRNA was also detected under in vivo and in vitro artificial decidualization. Estrogen, progesterone, and 8-bromoadenosine-cAMP could induce the expression of Tdo2 in the ovariectomized mouse uterus and uterine stromal cells. Tdo2 could regulate cell proliferation and stimulate the expression of decidual marker Dtprp in the uterine stromal cells and decidual cells. Overexpression of Tdo2 could upregulate the expression of Ahr, Cox2, and Vegf genes in uterine stromal cells, while Tdo2 inhibitor 680C91 could downregulate the expression of Cox2 and Vegf genes in uterine decidual cells. These data indicate that Tdo2 may play an important role during mouse decidualization and be regulated by estrogen, progesterone, and cAMP.

show abstract

Section: Discussionmentioning

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Differential expression and regulation of Tdo2 during mouse decidualization

Gao

Tian

et al. 2013

Journal of Endocrinology

View full text Add to dashboard Cite

show abstract

“…We did not observe obvious toxicity in mice treated with LM10 for 3 months. Moreover, mice genetically deficient for TDO2 were recently obtained and found viable and healthy (35). The main observation in those mice is a reduced anxiety, which may result from their highly increased serum levels of tryptophan.…”

Section: Discussionmentioning

confidence: 99%

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.

506

532

View full text Add to dashboard Cite

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...

show abstract

“…Recent studies have indicated that other metabolic fates of Trp in brain could also modulate behavior (reviewed in Ref. 39), most notably its conversion to the neuroactive metabolite kynurenic acid (KYNA) (30,34,36,39,81).…”

mentioning

confidence: 99%

Branched-chain amino acids alter neurobehavioral function in rats

Coppola

Wenner²,

Ilkayeva³

et al. 2013

American Journal of Physiology-Endocrinology and Metabolism

View full text Add to dashboard Cite

Newgard CB. Branched-chain amino acids alter neurobehavioral function in rats. Am J Physiol Endocrinol Metab 304: E405-E413, 2013. First published December 18, 2012 doi:10.1152/ajpendo.00373.2012.-Recently, we have described a strong association of branched-chain amino acids (BCAA) and aromatic amino acids (AAA) with obesity and insulin resistance. In the current study, we have investigated the potential impact of BCAA on behavioral functions. We demonstrate that supplementation of either a high-sucrose or a high-fat diet with BCAA induces anxiety-like behavior in rats compared with control groups fed on unsupplemented diets. These behavioral changes are associated with a significant decrease in the concentration of tryptophan (Trp) in brain tissues and a consequent decrease in serotonin but no difference in indices of serotonin synaptic function. The anxiety-like behaviors and decreased levels of Trp in the brain of BCAA-fed rats were reversed by supplementation of Trp in the drinking water but not by administration of fluoxetine, a selective serotonin reuptake inhibitor, suggesting that the behavioral changes are independent of the serotonergic pathway of Trp metabolism. Instead, BCAA supplementation lowers the brain levels of another Trp-derived metabolite, kynurenic acid, and these levels are normalized by Trp supplementation. We conclude that supplementation of high-energy diets with BCAA causes neurobehavioral impairment. Since BCAA are elevated spontaneously in human obesity, our studies suggest a potential mechanism for explaining the strong association of obesity and mood disorders.branched-chain amino acids; tryptophan; mood disorders; obesity IN THE PAST FEW DECADES, changes in food consumption and sedentary living conditions have contributed to a worldwide obesity epidemic, including in the US, where more than 34% of adults are obese (44,45). Given the high prevalence of obesity and mood disorders, there is an increasing interest in the relationship of these two conditions (2,17,25,33,42,58,62) and in the concept that overnutrition may have a direct causal link to impairment of mental function.Recent studies have revealed that a cluster of metabolites comprised of the branched-chain amino acids (BCAA) leucine (Leu), isoleucine (Ile), and valine (Val) and their metabolites, as well as the aromatic amino acids (AAA) tyrosine (Tyr) and phenylalanine (Phe), are strongly associated with obesity and insulin resistance in humans (1,10,29,43,67,78). Moreover, a very similar metabolite cluster predicts incident type 2 diabetes in longitudinal studies in humans (64) and, when measured at baseline in obese subjects, also predicts improvement in insulin sensitivity in response to a dietary/behavioral weight loss intervention (63). These findings suggest the possibility that elevated BCAA could be linked to behavioral disorders.BCAA are transported from the blood into the central nervous system (CNS) through the blood-brain barrier (BBB) by the large neutral amino acid transporter 1 (LAT1) (47). LAT1 transports ...

show abstract

Tryptophan 2,3-dioxygenase is a key modulator of physiological neurogenesis and anxiety-related behavior in mice

Cited by 240 publications

References 51 publications

Differential expression and regulation of Tdo2 during mouse decidualization

Differential expression and regulation of Tdo2 during mouse decidualization

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

Branched-chain amino acids alter neurobehavioral function in rats

Contact Info

Product

Resources

About