Monitoring tryptophan metabolism in chronic immune activation

Schröcksnadel, Katharina; Wirleitner, Barbara; Winkler, Christiana; Fuchs, Dietmar

doi:10.1016/j.cca.2005.06.013

Cited by 503 publications

(461 citation statements)

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“…This phenomenon is quite unusual [16], since IDO is often regarded as a feedback mechanism to inflammation, which may be indicated by proinflammatory cytokines [6,8]. However, this finding corroborates our concept that proinflammatory DC cytokine production and IDO induction are separate processes [6].…”

Section: Discussionsupporting

confidence: 87%

“…IDO induction is generally believed to represent a feedback mechanism of APC activation [8]. This understanding is supported by the observation that neopterin, a guanosine triphosphate (GTP) cleavage product [13], has been found to be closely linked to IDO activity in a wide spectrum of conditions involving immune activation [14][15][16].In some recent reports, also prostaglandin E2 (PGE 2 ) was described to up-regulate IDO competence in human DCs [17,18]. Induction of IDO competence through PGE 2 occurred, like in human DC maturation [19,20], in concert with TNF-α.…”

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confidence: 95%

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Ambivalent effects of dendritic cells displaying prostaglandin E2‐induced indoleamine 2,3‐dioxygenase

et al. 2012

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Prostaglandin E2 (PGE 2 ), an abundantly produced lipid messenger in mammalian organisms, has been attributed to possess potent albeit ambivalent immunological functions. Recently, PGE 2 has been reported to stimulate the commonly believed immunosuppressive indoleamine 2,3-dioxygenase (IDO) pathway in human dendritic cells (DCs), but without promoting DC immunosuppressive activity. Here, we report that PGE 2 used as a DC maturation agent apparently has more diverse functions. PGE 2 -matured DCs acquired powerful IDO activity, which was sustained even after removing PGE 2 . These IDO-competent DCs were able to stimulate allogeneic T-cell proliferation, but achieved inhibitory activity as their content in DC/T-cell co-cultures increased. The DC inhibitory activity was reversed upon blockade of IDO activity, confirming that the suppressive effect was in fact mediated by IDO and occurred in a dose-dependent fashion. IDO-mediated T-cell suppression was restored upon re-stimulation of T cells in the absence of IDO activity, confirming its reversibility. T cells stimulated by PGE 2 -matured IDO-competent DCs were sensitized to produce multiple cytokines, comprising Th1, Th2, and Th17 phenotypes. Collectively, these data suggest that T cells stimulated by PGE 2 -matured DCs are not terminally differentiated and their ultimate type of response may be formed by microenvironmental conditions. Keywords: Human dendritic cells r IL-23 r Immunosuppression r Indoleamine 2,3-dioxygenase (IDO) r Prostaglandin E2 Supporting Information available online IntroductionThe intracellular enzyme indoleamine 2,3-dioxygenase (IDO) has a key function in tryptophan metabolism along the kynurenine pathway [1]. IDO's metabolic activity has been perceived to play a significant role in immune regulation. On the cellular level, the complementary effects of IDO-mediated metabolism, tryptophan starvation, and accumulation of immunomodulatory kynurenines Correspondence: Dr. Andreas Heitger e-mail: andreas.heitger@ccri.at at the antigen-presenting cell (APC)/T-cell synapse were proposed to effect regulation of T-cell activation and proliferation [1,2]. In fact, in the last decade, multiple studies corroborated the role of IDO in immune regulation and induction of tolerance (reviewed in [3,4]). IDO competence, i.e. IDO expression and activity [5,6], has been suggested to play a critical role in numerous clinical conditions entailing immune regulation, including tolerance induction in pregnancy [7], transplantation [8,9], and tumor immune evasion [10]. * These authors contributed equally to the work. Eur. J. Immunol. 2012Immunol. . 42: 1117Immunol. -1128 Effective induction of IDO competence is, by and large, restricted to cells of the monocyte/macrophage lineage and, in humans is predominantly found in dendritic cells (DCs) [4,11]. Numerous agents, most prominently interferon (IFN)-γ, have been described to induce IDO activity in DCs [12]. IDO induction is generally believed to represent a feedback mechanism of APC activation [8]. This understanding...

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Section: Discussionsupporting

confidence: 87%

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confidence: 95%

Ambivalent effects of dendritic cells displaying prostaglandin E2‐induced indoleamine 2,3‐dioxygenase

et al. 2012

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“…IDO enzyme activity can be calculated by using the KYN to TRP quotient. Accelerated TRP breakdown and elevated KYN/TRP concentrations have been shown in many diseases and closely correlate with concentrations of immune activation markers like neopterin [1,[9][10][11][12]. In these situations, inflammation-activated IDO is driving the TRP catabolism and not tryptophan dioxygenase, a hepatic enzyme that is regulated via tryptophan levels or glucocorticoids.…”

Section: Introductionmentioning

confidence: 99%

Serum tryptophan, kynurenine, phenylalanine, tyrosine and neopterin concentrations in 100 healthy blood donors

Geisler

Mayersbach²,

Becker

et al. 2015

Pteridines

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AbstractFormation of neopterin, a biomarker of the activated human immune system, is linked with tryptophan (TRP) and phenylalanine (PHE) metabolism. To obtain normal values, in this study, serum concentrations of neopterin as well as of TRP, PHE and their respective metabolites kynurenine (KYN) and tyrosine (TYR) were investigated in 100 successive blood donor serum specimens from the University Clinics of Innsbruck, Austria. In addition, nitrite concentrations were determined. Donors had passed anamnestic examination at entry and were therefore considered as healthy. The mean age of participants was 49±11.4 (mean±SD) years; 18% were older than 60 years. Both genders were included in the analysis. Neopterin concentrations measured by enzyme-linked immunosorbent assay were 5.9±1.6 nmol/L (mean±SD). Levels of amino acids and metabolites were determined by HPLC. Mean KYN and TRP concentrations were 1.78±0.42 μmol/L and 67.4±10.2 μmol/L, respectively. KYN to TRP ratio (KYN/TRP), an estimate for the activity of tryptophan-degrading enzyme indoleamine 2,3-dioxygenase, was 26.7±6.2 μmol/mmol. Mean PHE and TYR concentrations were 65.2±11.1 μmol/L and 90.6±22.9 μmol/L. PHE to TYR ratio (PHE/TYR), an estimate for the activity of PHE-converting enzyme phenylalanine hydroxylase, was 0.75±0.14 μmol/μmol. Nitrite concentrations, estimated by Griess-Ilosvay reagent, were 44.9±32.0 μmol/L. Males were taller and heavier than females (both p<0.01), but body mass index did not differ. Males presented with significantly higher TRP and TYR concentrations than females (both p<0.05). There existed significant correlations between neopterin and KYN (rs=0.368), KYN/TRP (rs=0.453), TYR (rs=–0.267; all p<0.01) and PHE/TYR (rs=0.236; p<0.05) concentrations. Data indicate that also in a population of healthy individuals an association exists between “low-grade” immune activation as is indicated by slightly higher neopterin concentrations and biochemical alterations in the amino acid metabolism. Although minor, such changes may interfere with psychoneuroimmunological regulatory networks and thus be of clinical relevance.

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“…In mammals, most of tryptophan was metabolized along the kynurenine pathway and tryptophan metabolism was closely correlated with pregnancy (Stone & Darlington 2002, Schröcksnadel et al 2006. During pregnancy, decreased tryptophan concentration and increased concentrations of kynurenines were observed in human plasma and in the uteri of mice and cows (Minatogawa et al 2003, Schröcksnadel et al 2006, Groebner et al 2011. Previous studies have found that tryptophan metabolism was mainly dependent on tryptophan 2,3-dioxygenase (Tdo2) and indoleamine 2,3-dioxygenase (Ido) (Stone & Darlington 2002).…”

Section: Introductionmentioning

confidence: 99%

Differential expression and regulation of Tdo2 during mouse decidualization

Gao

Tian

et al. 2013

Journal of Endocrinology

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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.

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Monitoring tryptophan metabolism in chronic immune activation

Cited by 503 publications

References 64 publications

Ambivalent effects of dendritic cells displaying prostaglandin E2‐induced indoleamine 2,3‐dioxygenase

Ambivalent effects of dendritic cells displaying prostaglandin E2‐induced indoleamine 2,3‐dioxygenase

Serum tryptophan, kynurenine, phenylalanine, tyrosine and neopterin concentrations in 100 healthy blood donors

Differential expression and regulation of Tdo2 during mouse decidualization

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