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An Observational Cohort Study of the Kynurenine to Tryptophan Ratio in Sepsis: Association with Impaired Immune and Microvascular Function

  • Christabelle J. Darcy ,

    Contributed equally to this work with: Christabelle J. Darcy, Joshua S. Davis

    Affiliation Global Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia

  • Joshua S. Davis ,

    Contributed equally to this work with: Christabelle J. Darcy, Joshua S. Davis

    Affiliations Global Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia, Division of Medicine, Royal Darwin Hospital, Darwin, Northern Territory, Australia

  • Tonia Woodberry,

    Affiliation Global Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia

  • Yvette R. McNeil,

    Affiliation Global Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia

  • Dianne P. Stephens,

    Affiliation Intensive Care Unit, Royal Darwin Hospital, Darwin, Northern Territory, Australia

  • Tsin W. Yeo,

    Affiliations Global Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia, Division of Medicine, Royal Darwin Hospital, Darwin, Northern Territory, Australia

  • Nicholas M. Anstey

    Nicholas.anstey@menzies.edu.au

    Affiliations Global Health Division, Menzies School of Health Research and Charles Darwin University, Darwin, Northern Territory, Australia, Division of Medicine, Royal Darwin Hospital, Darwin, Northern Territory, Australia

An Observational Cohort Study of the Kynurenine to Tryptophan Ratio in Sepsis: Association with Impaired Immune and Microvascular Function

  • Christabelle J. Darcy, 
  • Joshua S. Davis, 
  • Tonia Woodberry, 
  • Yvette R. McNeil, 
  • Dianne P. Stephens, 
  • Tsin W. Yeo, 
  • Nicholas M. Anstey
PLOS
x

Abstract

Both endothelial and immune dysfunction contribute to the high mortality rate in human sepsis, but the underlying mechanisms are unclear. In response to infection, interferon-γ activates indoleamine 2,3-dioxygenase (IDO) which metabolizes the essential amino acid tryptophan to the toxic metabolite kynurenine. IDO can be expressed in endothelial cells, hepatocytes and mononuclear leukocytes, all of which contribute to sepsis pathophysiology. Increased IDO activity (measured by the kynurenine to tryptophan [KT] ratio in plasma) causes T-cell apoptosis, vasodilation and nitric oxide synthase inhibition. We hypothesized that IDO activity in sepsis would be related to plasma interferon-γ, interleukin-10, T cell lymphopenia and impairment of microvascular reactivity, a measure of endothelial nitric oxide bioavailability. In an observational cohort study of 80 sepsis patients (50 severe and 30 non-severe) and 40 hospital controls, we determined the relationship between IDO activity (plasma KT ratio) and selected plasma cytokines, sepsis severity, nitric oxide-dependent microvascular reactivity and lymphocyte subsets in sepsis. Plasma amino acids were measured by high performance liquid chromatography and microvascular reactivity by peripheral arterial tonometry. The plasma KT ratio was increased in sepsis (median 141 [IQR 64–235]) compared to controls (36 [28–52]); p<0.0001), and correlated with plasma interferon-γ and interleukin-10, and inversely with total lymphocyte count, CD8+ and CD4+ T-lymphocytes, systolic blood pressure and microvascular reactivity. In response to treatment of severe sepsis, the median KT ratio decreased from 162 [IQR 100–286] on day 0 to 89 [65–139] by day 7; p = 0.0006) and this decrease in KT ratio correlated with a decrease in the Sequential Organ Failure Assessment score (p<0.0001). IDO-mediated tryptophan catabolism is associated with dysregulated immune responses and impaired microvascular reactivity in sepsis and may link these two fundamental processes in sepsis pathophysiology.

Introduction

Sepsis is a systemic inflammatory response to infection [1]. Despite advances in its management, severe sepsis still has a mortality rate of 30–50% [2], [3], [4]. Both immune and endothelial dysfunction are thought to contribute to the high mortality rate in sepsis [5], [6], however the underlying mechanisms are not completely understood.

Tryptophan is an essential amino acid that is central to cellular respiration [7] and neurotransmission [8], and is a key immune mediator. During inflammation, tryptophan is metabolised by indoleamine 2,3-dioxygenase (IDO) to the toxic metabolite kynurenine. IDO activity is measured by the ratio of kynurenine to tryptophan (the KT ratio). Endothelial cells, monocytes, renal tubular epithelial cells and hepatocytes express IDO in response to interferon-γ [9], [10], [11], [12], [13] and IL10 stabilises IDO expression [14].

IDO activity regulates a number of immune responses. Increased IDO activity inhibits T cell function [15] and proliferation [14], [16], [17] and contributes to T cell apoptosis [18]. Furthermore, elevated IDO activity inhibits nitric oxide synthase and vice versa [19], [20], [21]. Recent isotope studies have shown that systemic NO production is either reduced or unchanged in human sepsis compared with healthy controls [22], [23], [24].

In addition to regulating the immune response, IDO activity may also regulate endothelial function. Kynurenine, a metabolite of IDO, has recently been described as an endogenous vasorelaxing factor [9]. Increased IDO activity would therefore be expected to directly decrease systemic vascular resistance. Additionally, as IDO inhibits NOS, IDO may indirectly affect endothelial function by impairing NO-dependent microvascular reactivity. NO is essential for normal endothelial function and NO-dependent microvascular reactivity has been previously shown to be impaired in patients with sepsis, in proportion to disease severity [25], [26]. Finally, plasma kynurenine concentrations have been associated with markers of endothelial dysfunction in patients with end-stage renal disease [27].

IDO activity correlates with disease severity in patients with chronic inflammatory diseases such as human immunodeficiency virus [28], systemic lupus erythematosus [29] and malignancy [30], but little is known about IDO activity in acute inflammatory states. A raised KT ratio has recently been reported in patients with bacteremia [31].

We investigated the relationship between the KT ratio and disease severity in sepsis. We hypothesised that the KT ratio would be related to IFN-γ and IL10 concentrations, and inversely related to both T cell lymphopenia and microvascular reactivity, a measure of endothelial NO bioavailability.

Methods

Participants

We evaluated patients with sepsis and hospital controls who were part of a previously reported study of endothelial function in sepsis [25]. Sepsis patients had suspected or proven infection and the presence of two or more criteria for the systemic inflammatory response syndrome (SIRS) within the last 4 hours [1]. Severe sepsis patients had organ dysfunction or shock at the time of enrolment according to the American College of Chest Physicians/Society of Critical Care Medicine criteria [1], [32]. Sepsis severity was estimated using the Acute Physiology and Chronic Health Evaluation (APACHE) II score from the first 24 hours of admission and daily modified Sequential Organ Failure Assessment (SOFA) score [33]. Patients were enrolled within 24 hours of ICU admission or within 36 hours of ward admission. Control subjects were recruited from hospital patients who had not met SIRS criteria within the last 30 days and who had no clinical or laboratory evidence of inflammation or infection. Written informed consent was obtained from all participants or next of kin. All sepsis patients had undergone resuscitation and were haemodynamically stable at the time of study enrolment. The study was approved by the Human Research Ethics Committee of Menzies School of Health Research and the Department of Health and Community Services.

Blood collection and lymphocyte counts

Venous blood was collected in lithium heparin tubes at enrolment, day 2–4, and day 7 until discharge from the hospital or death. Whole blood differential white cell counts were measured by Coulter Counter. Lymphopenia was defined as an absolute lymphocyte count less than 1.2×103/µL [34]. Plasma was separated and stored at −80°C.

Lymphocytes were analysed in more detail in a subset of patients from whom samples were processed within 30 minutes of collection, matched for age and gender. Peripheral blood mononuclear cells were separated using Ficoll-Paque™ Plus (GE Healthcare Biosciences, Uppsala, Sweden) and cryopreserved in fetal calf serum and dimethyl sulfoxide. Cells were thawed and stained with appropriate antibodies and analysed on a FACSCalibur flow cytometer (Becton Dickinson Immunocytometry Systems, MA, USA). Antibodies were sourced from Biolegend, California, USA (CD3, CD16 and CD56) or BD Biosciences Pharmingen, California, USA (CD4 and CD8). Results were analysed using Flow Jo software (Tree Star, Oregon, USA). T cells were defined as CD3+ lymphocytes and natural killer cells were defined as CD3−CD16+CD56+ lymphocytes.

Tryptophan and kynurenine measurements

Plasma tryptophan and kynurenine concentrations were measured by High Pressure Liquid Chromatography (HPLC; Shimadzu, Kyoto, Japan) with UV (250 nm) and fluorescence (excitation 250 nm, emission 395 nm) detection, using a method modified from van Wandelen and Cohen [35]. The kynurenine to tryptophan (KT) ratio was calculated by dividing the kynurenine concentration (µmol/L) by the tryptophan concentration (µmol/L) and multiplying the quotient by 1000 [28], [36], [37].

Plasma cytokine measurements

Concentrations of plasma IFN-γ, IL6 and IL10 were determined using a cytometric bead array (Human Th1/Th2 Cytokine Kit II, BD Biosciences Pharmingen, CA, USA) and a FACSCalibur flow cytometer (Becton Dickinson Immunocytometry Systems, MA, USA). Results were analysed using FCAP array version 1.0.1 (Soft Flow Hungary for Becton Dickinson Biosciences). The lower limits of detection (LLD) of the assay were 2.5 pg/mL for IFN-γ and 10 pg/mL for IL6 and IL10. Values below the LLD were assigned a value halfway between zero and the LLD for statistical analysis. Cytokines were only measured if plasma had been frozen within 2 hours of collection.

Measurement of endothelial function

Sepsis patients underwent serial bedside reactive hyperemia peripheral arterial tonometry (RH-PAT) measurements at enrolment, day 2–4, and day 7 [25]. Control patients had the same assessment at a single time point. RH-PAT (Itamar Medical, Caesarea, Israel) is a non-invasive operator-independent method of assessing endothelial function. Endothelial function is defined by the ability of blood vessels to vasodilate in response to an ischemic stress, which invasive studies have demonstrated to be dependent on endothelial cell NO production [38]. RH-PAT is at least 50% NO-dependent [39]. RH-PAT uses finger probes to measure digital pulse wave amplitude detected by a pressure transducer [40], and has been validated against the more operator-dependent flow-mediated dilatation method [41] and with endothelial function in other vascular beds [42].

Statistical methods

Predefined groups for analysis were severe sepsis, non-severe sepsis (meaning sepsis without evidence of organ dysfunction or shock at enrolment), and hospital controls. Continuous parametric variables were compared using Student's t-test or ANOVA while continuous non-parametric variables were compared using Mann-Whitney, Kruskal-Wallis or Wilcoxon tests as appropriate. Correlations were examined using Pearson's or Spearman's tests for parametric and non-parametric data respectively. As SOFA score was highly right-skewed and no transformation gave a normal distribution, Kendall's tau coefficient for partial correlation was used for multivariate analysis involving SOFA [43]. Linear mixed-effects models were used to examine longitudinal correlations. A 2-sided p-value of <0.05 was considered significant. Analyses were performed using Stata version 10.0 (Stata Corp TX, USA) and Prism version 5.01 (GraphPad Software, CA, USA).

Results

Patients

The study included 50 patients with severe sepsis, 30 with non-severe sepsis and 40 hospital controls. The three groups did not differ significantly in age or gender (Table 1). Ninety percent of severe sepsis patients and all non-severe sepsis patients were either orally or enterally fed at the time of enrolment; none were receiving parenteral nutrition.

IDO activity and sepsis severity

Plasma tryptophan concentrations were significantly reduced in patients with sepsis (p<0.0001, Figure 1 and Table 2). In all sepsis patients, plasma tryptophan was inversely related to SOFA score (r = −0.45, p<0.0001). There was no difference in the baseline plasma tryptophan concentrations among severe sepsis patients who were orally fed (n = 29), enterally fed (n = 16) or who were nil by mouth (n = 5).

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Figure 1. Plasma assessment of tryptophan catabolism.

The concentration of plasma tryptophan (Fig. 1A), kynurenine (Fig. 1B) and the KT ratio (Fig. 1C) in 50 severe sepsis patients, 30 non-severe sepsis patients and 40 hospital controls. Fig. 1D shows the KT ratio in severe sepsis patients on admission (n = 50), day 2 (n = 34) and day 7 (n = 16). The KT ratio is determined by dividing the plasma kynurenine concentration (µmol/L) by the plasma tryptophan concentration (µmol/L) and multiplying the quotient by 1000. Horizontal lines represent median values for the group. P value analysis in Figs. 1A–C used a Mann Whitney test, and in Fig. 1D, a paired Wilcoxon test.

https://doi.org/10.1371/journal.pone.0021185.g001

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Table 2. Immunological characteristics of participants (median and interquartile range).

https://doi.org/10.1371/journal.pone.0021185.t002

Conversely, plasma kynurenine concentrations were elevated in sepsis patients compared to hospital controls (p<0.0001, Figure 1 and Table 2). In all sepsis patients, plasma kynurenine correlated with SOFA score (r = 0.34, p = 0.005). As kynurenine is renally excreted and accumulates in renal failure [44], [45], kynurenine concentrations were tested for relationships with renal impairment. Kynurenine concentrations were significantly higher in patients requiring continuous renal replacement therapy (CRRT) (median 4.5 µmol [IQR 4–5.3]) than in patients not receiving CRRT (2.8 µmol [2.1–4.4]; p = 0.03). In all sepsis patients, kynurenine concentration correlated with plasma creatinine (r = 0.41, p = 0.0002). Nevertheless, the association between plasma kynurenine concentration and SOFA score remained significant even after controlling for creatinine (ktau = 0.24, p<0.01).

IDO activity was significantly increased in sepsis patients (median KT ratio 141 [IQR 64–235]) compared to controls (36 [28–52]) (p<0.0001) and in severe sepsis compared to non-severe sepsis (p = 0.0006, Table 2). The baseline KT ratio correlated with APACHE II (rs = 0.51, p<0.0001) and total SOFA scores (rs = 0.54, p<0.0001) in sepsis patients. The KT ratio positively correlated with the hepatic (rs = 0.28, p = 0.01), renal (rs = 0.53, p<0.0001), cardiovascular (rs = 0.42, p<0.0001) and respiratory (rs = 0.36, p = 0.0009) components of the SOFA score but not the coagulation component (rs = 0.13, p = ns).

Of the 80 sepsis patients, 6 died by day 28 of the study. The baseline KT ratio in patients who died (median 270 [IQR 102–431] was not statistically significantly different to those who survived (138 [63–232]; p = 0.2).

In longitudinal analysis of severe sepsis, the KT ratio significantly decreased between day 0 (median 162 [IQR 100–286]) and day 7 (89 [65–139]), p = 0.0006); Figure 1D. Among all sepsis patients, decrease in KT ratio correlated with decrease in SOFA score over time (p<0.0001).

IDO activity and plasma cytokines

Plasma IFN-γ, IL6 and IL10 were all significantly increased in patients with sepsis (Table 2). Plasma concentrations of IL1, IL2, IL4 and tumour necrosis factor-α were not significantly increased in this cohort and were not analysed further. Both IL6 and IL10 positively correlated with SOFA score (rs = 0.55, p<0.0001 and rs = 0.55, p<0.0001 respectively) but there was no association between IFN-γ and SOFA score.

In sepsis patients, the KT ratio correlated with plasma IFN-γ (rs = 0.44, p = 0.0002), IL6 (rs = 0.49, p<0.0001) and IL10 (rs = 0.62, p<0.0001). The associations between KT ratio and IL6 and IL10 remained significant after controlling for SOFA score (ktau = 0.30, p<0.003 and ktau = 0.45, p<0.0001 respectively).

In a univariate mixed effects model, the decrease in KT ratio over time correlated with the decrease in IL6 (p<0.0001) and IL10 (p<0.0001) between day 0 and day 7. In a multivariate model, these relationships remained significant after controlling for change in SOFA score (IL6 p = 0.009; IL10 p = 0.02).

IDO activity and lymphocyte counts

Sepsis patients had increased white blood cell counts (p<0.0001) primarily due to increased circulating neutrophils (p<0.05; Table 2), which proliferate in response to bacterial infections [46]. Conversely, sepsis patients had significantly lower total lymphocyte counts compared with hospital controls (p<0.0001, Table 2). In all sepsis patients the baseline KT ratio was weakly associated with absolute lymphocyte count (rp = 0.26, p = 0.02). In a linear mixed effects model, absolute lymphocyte count increased as the KT ratio decreased over time (p = 0.001). This relationship persisted after controlling for SOFA score (p = 0.008). When all subjects were grouped according to lymphopenia, lymphopenic patients (n = 63) had a median KT ratio of 128 [IQR 63–236], compared with 59 [33–86] in non-lymphopenic patients (n = 57) (p<0.0001).

As IDO activity contributes to T cell apoptosis [18], we examined the relationship between KT ratio and lymphocyte subsets. Peripheral blood mononuclear cells were analysed from 23 of the 80 sepsis patients whose blood had been processed within 30 minutes of collection. This subset of patients was representative of the cohort in terms of age, gender distribution, total lymphocyte count and KT ratio. In this subset of patients, the KT ratio negatively correlated with absolute numbers of lymphocytes (rp = −0.54, p = 0.007), T cells (rp = −0.53, p = 0.01), CD4+ T cells (rp = −0.50, p = 0.01), CD8+ T cells (rp = −0.49, p = 0.02) and natural killer cells (rp = −0.46, p = 0.03) (Table 2).

IDO activity and endothelial function

In sepsis, the KT ratio at baseline correlated inversely with NO-dependent microvascular reactivity (rs = −0.45, p = 0.001) even after controlling for disease severity (using SOFA score; p = 0.001). In a multivariate mixed effects model controlling for SOFA score, improvement in KT ratio between day 0 and day 7 correlated with improvement in microvascular reactivity (p = 0.001). In all sepsis patients, there was an inverse association between the baseline KT ratio and mean arterial pressure (rs = −0.29, p = 0.009) and diastolic blood pressure (rs = −0.29, p = 0.01) but no association with systolic blood pressure.

Discussion

IDO activity is increased in sepsis, in proportion to disease severity. IDO-mediated tryptophan catabolism is associated with dysregulated immune responses and impaired microvascular reactivity in sepsis. IFN-γ and IL10 are associated with, and may contribute to, increased IDO activity in sepsis. The independent inverse longitudinal association with total lymphocyte counts suggests a potential role in sepsis-associated lymphopenia. Similarly, the independent inverse association between the KT ratio and microvascular reactivity suggests that IDO activity may also contribute to impaired endothelial function in sepsis. Based on these associations we propose a model of interpretation outlined in Figure 2.

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Figure 2. Proposed model of tryptophan catabolism in sepsis.

IDO = Indoleamine 2,3-dioxygenase, IL6 = interleukin-6, IL10 = interleukin-10, IFN-γ = interferon gamma and NO = nitric oxide.

https://doi.org/10.1371/journal.pone.0021185.g002

Increased expression of IFN-γ [47], IL6 [48], [49] and IL10 [14] have each been associated with increased tryptophan catabolism by IDO in other disease states. In sepsis patients in our study, IFN-γ concentration correlated with the KT ratio only at baseline, whereas IL6 and IL10 correlated with the KT ratio both at baseline and longitudinally. Our findings agree with the in vitro literature, where IFN-γ induces IDO [10], [47]. Although under certain conditions, IL-10 has been reported to suppress IDO activity [50], our findings support the majority of in vitro studies which have shown that IL-10 induces or stabilises IDO [14], [51], [52], [53]. The high IFN-γ associated with early sepsis [54] may lead to increased IDO activity while high IL10 may sustain or potentially enhance IDO activity [53] throughout the course of the disease. The role of IL6 in IDO expression is unclear. Orabona et al. suggest that IL6 inhibits IDO activity by increasing murine dendritic cell SOCS3 expression, which drives IDO breakdown [55]. On the other hand, a low tryptophan environment created by IDO activity stabilises IL6 mRNA and increases IL6 responses [56]. Given the conflicting evidence in these and other studies regarding IL6 and IDO, we investigated the relationship between the KT ratio and IL6 in sepsis patients. The strong positive correlation between plasma KT ratio and IL6 concentration is consistent with findings in murine models of sepsis where IDO−/− mice or mice treated with IDO inhibitors have lower plasma IL6 concentrations [57], [58].

We report that the high KT ratio in sepsis is associated with a decreased lymphocyte count, independent of disease severity, a finding similar to that found in patients with trauma [37], human immunodeficiency virus [28] and cancer [59]. Previous studies in sepsis have associated lymphopenia with disease severity [60], duration of ICU stay [60] and mortality [61] and prevention of lymphocyte apoptosis improves survival in animal models of sepsis [62], [63], [64], [65]. T cells co-cultured with IDO-producing cells have reduced proliferation and increased death [66], [67]. Both high kynurenine concentrations and low tryptophan concentrations appear to contribute to T cell death. In vivo, kynurenine treatment in mice depletes overall thymocyte counts and, in vitro, thymocytes die of apoptosis when cultured in media with kynurenines [18]. Furthermore, T cells cultured in low tryptophan media have reduced proliferation and increased apoptosis via activated GCN2 kinase [68], [69]. These in vitro studies suggest a potential mechanism through which increased IDO activity may contribute to lymphopenia and its deleterious consequences in sepsis.

IDO activity regulates vascular tone in sepsis. In this study IDO activity in sepsis patients correlated with diastolic blood pressure but not systolic blood pressure. This is consistent with the recent finding that kynurenine is a vascular relaxation factor [9]. Another important regulator of endothelial function in sepsis is NO. There is significant cross-talk between IDO and NOS, with IDO activity inhibiting both expression and activity of NOS [19], [20], [21] and vice versa. We found the KT ratio in sepsis is inversely associated with microvascular reactivity as measured by RH-PAT, which is at least 50% dependent on endothelial NO production [70]. Increased IDO activity in sepsis may regulate vascular tone directly, via the vasorelaxing effects of kynurenine, and indirectly, by impairing NO-dependent microvascular reactivity. Increased plasma kynurenine concentrations may further impede endothelial function in sepsis by mediating adhesion of monocytes and neutrophils to the vascular endothelium [71].

A limitation of this study is that we did not directly measure IDO expression. However, the KT ratio is an established measure of systemic IDO activity [28], [72] with tissue IDO expression and activity directly correlated with plasma KT ratio in multiple human disease states, including celiac disease [73], hepatitis C [11] and pre-eclampsia [74]. There are several possible sources of IDO activity in sepsis patients including the endothelium, kidney, liver, lungs and leukocytes [9], [10], [11], [12], [13], [53], although a recent study was unable to detect spontaneous IDO expression in PBMC from sepsis patients [75]. Importantly, the effects of the high KT ratio in sepsis on immune function and endothelial function would be the same whether the high KT ratio was the result of increased IDO activity alone or in combination with decreased feeding and impaired renal excretion of kynurenine. Furthermore, it is unlikely that nutritional deficiency and renal impairment accounted for the differences we found, because controlling for these factors made no difference to our results.

In our study the KT ratio was not significantly associated with mortality. Consistent with the previously reported low mortality from severe sepsis in our ICU [32], [76], there were few deaths in our study. This suggests that our study was under-powered to examine the relationship between IDO activity and mortality. However, in a study with higher numbers of deaths, Hattunen and colleagues found a clear association between plasma KT ratio and risk of death in sepsis [31].

The generation of a low tryptophan environment may be a maladaptive host response to infection. While growth of some bacterial species is inhibited by low tryptophan [77], most can synthesize tryptophan [78] and others have specialized tryptophan transport systems [79]. In murine models of sepsis, IDO−/− mice have significantly increased survival compared to wild type mice [58] and treatment of wild-type mice with IDO inhibitors such as 1-methyl-tryptophan [58] or ethyl pyruvate also significantly increase survival [57]. The KT ratio is significantly higher in bacteremic patients with a fatal outcome [31] and we and others have demonstrated that the KT ratio is associated with disease severity in sepsis [31], [75], [80]. Together, this evidence supports the hypothesis that increased IDO activity is a deleterious host response in human sepsis. IDO inhibitors are being considered as potential adjunctive cancer treatments [81] and these treatments may also have therapeutic potential in sepsis.

Conclusion

IDO activity is elevated in sepsis and associated with disease severity, T cell lymphopenia and microvascular dysfunction. Because excessive IDO activity is associated with both immune and endothelial dysfunction, increased tryptophan catabolism may link these two key aspects of sepsis pathophysiology. Modulation of IDO activity warrants investigation as a therapeutic strategy in sepsis.

Acknowledgments

We thank Kim Piera, Catherine Jones and Barbara MacHunter for laboratory assistance; Jane Thomas, Mark McMillan, Karl Blenk, Antony Van Asche, Steven Tong and Paulene Kittler for RH-PAT measurements and sample collection; Alex Humphrey for database assistance; Joseph McDonnell for statistical advice; David Celermajer for advice on vascular function assessments and contribution to the design of the original study, and the medical and nursing staff of the Royal Darwin Hospital Intensive Care Unit, Division of Medicine and Hospital in the Home.

Author Contributions

Conceived and designed the experiments: CJD JSD TW YRM DPS TWY NMA. Performed the experiments: JSD DPS CJD TW YRM. Analyzed the data: CJD JSD TW NMA. Wrote the paper: CJD JSD TW YRM DPS TWY NMA.

References

  1. 1. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, et al. (1992) Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 101: 1644–1655.RC BoneRA BalkFB CerraRP DellingerAM Fein1992Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine.Chest10116441655
  2. 2. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, et al. (2001) Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 29: 1303–1310.DC AngusWT Linde-ZwirbleJ. LidickerG. ClermontJ. Carcillo2001Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care.Crit Care Med2913031310
  3. 3. Finfer S, Bellomo R, Lipman J, French C, Dobb G, et al. (2004) Adult-population incidence of severe sepsis in Australian and New Zealand intensive care units. Intensive Care Med 30: 589–596.S. FinferR. BellomoJ. LipmanC. FrenchG. Dobb2004Adult-population incidence of severe sepsis in Australian and New Zealand intensive care units.Intensive Care Med30589596
  4. 4. Blanco J, Muriel-Bombin A, Sagredo V, Taboada F, Gandia F, et al. (2008) Incidence, organ dysfunction and mortality in severe sepsis: a Spanish multicentre study. Crit Care 12: R158.J. BlancoA. Muriel-BombinV. SagredoF. TaboadaF. Gandia2008Incidence, organ dysfunction and mortality in severe sepsis: a Spanish multicentre study.Crit Care12R158
  5. 5. Hotchkiss RS, Karl IE (2003) The pathophysiology and treatment of sepsis. N Engl J Med 348: 138–150.RS HotchkissIE Karl2003The pathophysiology and treatment of sepsis.N Engl J Med348138150
  6. 6. Aird WC (2003) The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome. Blood 101: 3765–3777.WC Aird2003The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome.Blood10137653777
  7. 7. Ellinger P, Abdel Kader MM (1947) Tryptophane as precursor of nicotinamide in mammals. Nature 160: 675.P. EllingerMM Abdel Kader1947Tryptophane as precursor of nicotinamide in mammals.Nature160675
  8. 8. Fernstrom JD, Wurtman RJ (1971) Brain serotonin content: physiological dependence on plasma tryptophan levels. Science 173: 149–152.JD FernstromRJ Wurtman1971Brain serotonin content: physiological dependence on plasma tryptophan levels.Science173149152
  9. 9. Wang Y, Liu H, McKenzie G, Witting PK, Stasch JP, et al. (2010) Kynurenine is an endothelium-derived relaxing factor produced during inflammation. Nat Med 16: 279–285.Y. WangH. LiuG. McKenziePK WittingJP Stasch2010Kynurenine is an endothelium-derived relaxing factor produced during inflammation.Nat Med16279285
  10. 10. Carlin JM, Borden EC, Sondel PM, Byrne GI (1989) Interferon-induced indoleamine 2,3-dioxygenase activity in human mononuclear phagocytes. J Leukoc Biol 45: 29–34.JM CarlinEC BordenPM SondelGI Byrne1989Interferon-induced indoleamine 2,3-dioxygenase activity in human mononuclear phagocytes.J Leukoc Biol452934
  11. 11. Larrea E, Riezu-Boj JI, Gil-Guerrero L, Casares N, Aldabe R, et al. (2007) Upregulation of indoleamine 2,3-dioxygenase in hepatitis C virus infection. J Virol 81: 3662–3666.E. LarreaJI Riezu-BojL. Gil-GuerreroN. CasaresR. Aldabe2007Upregulation of indoleamine 2,3-dioxygenase in hepatitis C virus infection.J Virol8136623666
  12. 12. Iwamoto N, Ito H, Ando K, Ishikawa T, Hara A, et al. (2009) Upregulation of indoleamine 2,3-dioxygenase in hepatocyte during acute hepatitis caused by hepatitis B virus-specific cytotoxic T lymphocytes in vivo. Liver Int 29: 277–283.N. IwamotoH. ItoK. AndoT. IshikawaA. Hara2009Upregulation of indoleamine 2,3-dioxygenase in hepatocyte during acute hepatitis caused by hepatitis B virus-specific cytotoxic T lymphocytes in vivo.Liver Int29277283
  13. 13. Mohib K, Guan Q, Diao H, Du C, Jevnikar AM (2007) Proapoptotic activity of indoleamine 2,3-dioxygenase expressed in renal tubular epithelial cells. Am J Physiol Renal Physiol 293: F801–812.K. MohibQ. GuanH. DiaoC. DuAM Jevnikar2007Proapoptotic activity of indoleamine 2,3-dioxygenase expressed in renal tubular epithelial cells.Am J Physiol Renal Physiol293F801812
  14. 14. Munn DH, Sharma MD, Lee JR, Jhaver KG, Johnson TS, et al. (2002) Potential regulatory function of human dendritic cells expressing indoleamine 2,3-dioxygenase. Science 297: 1867–1870.DH MunnMD SharmaJR LeeKG JhaverTS Johnson2002Potential regulatory function of human dendritic cells expressing indoleamine 2,3-dioxygenase.Science29718671870
  15. 15. Fallarino F, Grohmann U, You S, McGrath BC, Cavener DR, et al. (2006) The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor zeta-chain and induce a regulatory phenotype in naive T cells. J Immunol 176: 6752–6761.F. FallarinoU. GrohmannS. YouBC McGrathDR Cavener2006The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor zeta-chain and induce a regulatory phenotype in naive T cells.J Immunol17667526761
  16. 16. Munn DH, Shafizadeh E, Attwood JT, Bondarev I, Pashine A, et al. (1999) Inhibition of T cell proliferation by macrophage tryptophan catabolism. J Exp Med 189: 1363–1372.DH MunnE. ShafizadehJT AttwoodI. BondarevA. Pashine1999Inhibition of T cell proliferation by macrophage tryptophan catabolism.J Exp Med18913631372
  17. 17. Boasso A, Herbeuval JP, Hardy AW, Anderson SA, Dolan MJ, et al. (2007) HIV inhibits CD4+ T-cell proliferation by inducing indoleamine 2,3-dioxygenase in plasmacytoid dendritic cells. Blood 109: 3351–3359.A. BoassoJP HerbeuvalAW HardySA AndersonMJ Dolan2007HIV inhibits CD4+ T-cell proliferation by inducing indoleamine 2,3-dioxygenase in plasmacytoid dendritic cells.Blood10933513359
  18. 18. Fallarino F, Grohmann U, Vacca C, Bianchi R, Orabona C, et al. (2002) T cell apoptosis by tryptophan catabolism. Cell Death Differ 9: 1069–1077.F. FallarinoU. GrohmannC. VaccaR. BianchiC. Orabona2002T cell apoptosis by tryptophan catabolism.Cell Death Differ910691077
  19. 19. Sekkai D, Guittet O, Lemaire G, Tenu JP, Lepoivre M (1997) Inhibition of nitric oxide synthase expression and activity in macrophages by 3-hydroxyanthranilic acid, a tryptophan metabolite. Arch Biochem Biophys 340: 117–123.D. SekkaiO. GuittetG. LemaireJP TenuM. Lepoivre1997Inhibition of nitric oxide synthase expression and activity in macrophages by 3-hydroxyanthranilic acid, a tryptophan metabolite.Arch Biochem Biophys340117123
  20. 20. Chiarugi A, Rovida E, Dello Sbarba P, Moroni F (2003) Tryptophan availability selectively limits NO-synthase induction in macrophages. J Leukoc Biol 73: 172–177.A. ChiarugiE. RovidaP. Dello SbarbaF. Moroni2003Tryptophan availability selectively limits NO-synthase induction in macrophages.J Leukoc Biol73172177
  21. 21. Samelson-Jones BJ, Yeh SR (2006) Interactions between nitric oxide and indoleamine 2,3-dioxygenase. Biochemistry 45: 8527–8538.BJ Samelson-JonesSR Yeh2006Interactions between nitric oxide and indoleamine 2,3-dioxygenase.Biochemistry4585278538
  22. 22. Luiking YC, Poeze M, Ramsay G, Deutz NE (2009) Reduced citrulline production in sepsis is related to diminished de novo arginine and nitric oxide production. Am J Clin Nutr 89: 142–152.YC LuikingM. PoezeG. RamsayNE Deutz2009Reduced citrulline production in sepsis is related to diminished de novo arginine and nitric oxide production.Am J Clin Nutr89142152
  23. 23. Kao CC, Bandi V, Guntupalli KK, Wu M, Castillo L, et al. (2009) Arginine, citrulline and nitric oxide metabolism in sepsis. Clin Sci (Lond) 117: 23–30.CC KaoV. BandiKK GuntupalliM. WuL. Castillo2009Arginine, citrulline and nitric oxide metabolism in sepsis.Clin Sci (Lond)1172330
  24. 24. Villalpando S, Gopal J, Balasubramanyam A, Bandi VP, Guntupalli K, et al. (2006) In vivo arginine production and intravascular nitric oxide synthesis in hypotensive sepsis. Am J Clin Nutr 84: 197–203.S. VillalpandoJ. GopalA. BalasubramanyamVP BandiK. Guntupalli2006In vivo arginine production and intravascular nitric oxide synthesis in hypotensive sepsis.Am J Clin Nutr84197203
  25. 25. Davis JS, Yeo TW, Thomas JH, McMillan M, Darcy CJ, et al. (2009) Sepsis-associated microvascular dysfunction measured by peripheral arterial tonometry: an observational study. Crit Care 13: R155.JS DavisTW YeoJH ThomasM. McMillanCJ Darcy2009Sepsis-associated microvascular dysfunction measured by peripheral arterial tonometry: an observational study.Crit Care13R155
  26. 26. Vaudo G, Marchesi S, Siepi D, Brozzetti M, Lombardini R, et al. (2008) Human endothelial impairment in sepsis. Atherosclerosis 197: 747–752.G. VaudoS. MarchesiD. SiepiM. BrozzettiR. Lombardini2008Human endothelial impairment in sepsis.Atherosclerosis197747752
  27. 27. Pawlak K, Domaniewski T, Mysliwiec M, Pawlak D (2009) Kynurenines and oxidative status are independently associated with thrombomodulin and von Willebrand factor levels in patients with end-stage renal disease. Thromb Res 124: 452–457.K. PawlakT. DomaniewskiM. MysliwiecD. Pawlak2009Kynurenines and oxidative status are independently associated with thrombomodulin and von Willebrand factor levels in patients with end-stage renal disease.Thromb Res124452457
  28. 28. Huengsberg M, Winer JB, Gompels M, Round R, Ross J, et al. (1998) Serum kynurenine-to-tryptophan ratio increases with progressive disease in HIV-infected patients. Clin Chem 44: 858–862.M. HuengsbergJB WinerM. GompelsR. RoundJ. Ross1998Serum kynurenine-to-tryptophan ratio increases with progressive disease in HIV-infected patients.Clin Chem44858862
  29. 29. Widner B, Sepp N, Kowald E, Ortner U, Wirleitner B, et al. (2000) Enhanced tryptophan degradation in systemic lupus erythematosus. Immunobiology 201: 621–630.B. WidnerN. SeppE. KowaldU. OrtnerB. Wirleitner2000Enhanced tryptophan degradation in systemic lupus erythematosus.Immunobiology201621630
  30. 30. Huang A, Fuchs D, Widner B, Glover C, Henderson DC, et al. (2002) Serum tryptophan decrease correlates with immune activation and impaired quality of life in colorectal cancer. Br J Cancer 86: 1691–1696.A. HuangD. FuchsB. WidnerC. GloverDC Henderson2002Serum tryptophan decrease correlates with immune activation and impaired quality of life in colorectal cancer.Br J Cancer8616911696
  31. 31. Huttunen R, Syrjanen J, Aittoniemi J, Oja SS, Raitala A, et al. (2009) High activity of indoleamine 2,3 dioxygenase enzyme predicts disease severity and case fatality in bacteremic patients. Shock. R. HuttunenJ. SyrjanenJ. AittoniemiSS OjaA. Raitala2009High activity of indoleamine 2,3 dioxygenase enzyme predicts disease severity and case fatality in bacteremic patients.Shock
  32. 32. Stephens DP, Thomas JH, Higgins A, Bailey M, Anstey NM, et al. (2008) Randomized, double-blind, placebo-controlled trial of granulocyte colony-stimulating factor in patients with septic shock. Crit Care Med 36: 448–454.DP StephensJH ThomasA. HigginsM. BaileyNM Anstey2008Randomized, double-blind, placebo-controlled trial of granulocyte colony-stimulating factor in patients with septic shock.Crit Care Med36448454
  33. 33. Vincent JL, de Mendonca A, Cantraine F, Moreno R, Takala J, et al. (1998) Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter, prospective study. Working group on “sepsis-related problems” of the European Society of Intensive Care Medicine. Crit Care Med 26: 1793–1800.JL VincentA. de MendoncaF. CantraineR. MorenoJ. Takala1998Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter, prospective study. Working group on “sepsis-related problems” of the European Society of Intensive Care Medicine.Crit Care Med2617931800
  34. 34. Hotchkiss RS, Swanson PE, Freeman BD, Tinsley KW, Cobb JP, et al. (1999) Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Crit Care Med 27: 1230–1251.RS HotchkissPE SwansonBD FreemanKW TinsleyJP Cobb1999Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction.Crit Care Med2712301251
  35. 35. van Wandelen C, Cohen SA (1997) Using quaternary high-performance liquid chromatography eluent systems for separating 6-aminoquionolyl-N-hydroxysuccinyl carbamate-derivatized amino acid mixtures. J Chromatogr A 763: 11–22.C. van WandelenSA Cohen1997Using quaternary high-performance liquid chromatography eluent systems for separating 6-aminoquionolyl-N-hydroxysuccinyl carbamate-derivatized amino acid mixtures.J Chromatogr A7631122
  36. 36. Zangerle R, Widner B, Quirchmair G, Neurauter G, Sarcletti M, et al. (2002) Effective antiretroviral therapy reduces degradation of tryptophan in patients with HIV-1 infection. Clin Immunol 104: 242–247.R. ZangerleB. WidnerG. QuirchmairG. NeurauterM. Sarcletti2002Effective antiretroviral therapy reduces degradation of tryptophan in patients with HIV-1 infection.Clin Immunol104242247
  37. 37. Pellegrin K, Neurauter G, Wirleitner B, Fleming AW, Peterson VM, et al. (2005) Enhanced enzymatic degradation of tryptophan by indoleamine 2,3-dioxygenase contributes to the tryptophan-deficient state seen after major trauma. Shock 23: 209–215.K. PellegrinG. NeurauterB. WirleitnerAW FlemingVM Peterson2005Enhanced enzymatic degradation of tryptophan by indoleamine 2,3-dioxygenase contributes to the tryptophan-deficient state seen after major trauma.Shock23209215
  38. 38. Deanfield JE, Halcox JP, Rabelink TJ (2007) Endothelial function and dysfunction: testing and clinical relevance. Circulation 115: 1285–1295.JE DeanfieldJP HalcoxTJ Rabelink2007Endothelial function and dysfunction: testing and clinical relevance.Circulation11512851295
  39. 39. Kuvin JT, Mammen A, Mooney P, Alsheikh-Ali AA, Karas RH (2007) Assessment of peripheral vascular endothelial function in the ambulatory setting. Vasc Med 12: 13–16.JT KuvinA. MammenP. MooneyAA Alsheikh-AliRH Karas2007Assessment of peripheral vascular endothelial function in the ambulatory setting.Vasc Med121316
  40. 40. Celermajer DS (2008) Reliable endothelial function testing: at our fingertips? Circulation 117: 2428–2430.DS Celermajer2008Reliable endothelial function testing: at our fingertips?Circulation11724282430
  41. 41. Kuvin JT, Patel AR, Sliney KA, Pandian NG, Sheffy J, et al. (2003) Assessment of peripheral vascular endothelial function with finger arterial pulse wave amplitude. Am Heart J 146: 168–174.JT KuvinAR PatelKA SlineyNG PandianJ. Sheffy2003Assessment of peripheral vascular endothelial function with finger arterial pulse wave amplitude.Am Heart J146168174
  42. 42. Bonetti PO, Pumper GM, Higano ST, Holmes DR Jr, Kuvin JT, et al. (2004) Noninvasive identification of patients with early coronary atherosclerosis by assessment of digital reactive hyperemia. J Am Coll Cardiol 44: 2137–2141.PO BonettiGM PumperST HiganoDR Holmes JrJT Kuvin2004Noninvasive identification of patients with early coronary atherosclerosis by assessment of digital reactive hyperemia.J Am Coll Cardiol4421372141
  43. 43. Gibbons J, Chakraborti S (2003) Nonparametric Statistical Inference. Marcel Dekker. J. GibbonsS. Chakraborti2003Nonparametric Statistical InferenceMarcel Dekker
  44. 44. Pawlak D, Tankiewicz A, Matys T, Buczko W (2003) Peripheral distribution of kynurenine metabolites and activity of kynurenine pathway enzymes in renal failure. J Physiol Pharmacol 54: 175–189.D. PawlakA. TankiewiczT. MatysW. Buczko2003Peripheral distribution of kynurenine metabolites and activity of kynurenine pathway enzymes in renal failure.J Physiol Pharmacol54175189
  45. 45. Schefold JC, Zeden JP, Fotopoulou C, von Haehling S, Pschowski R, et al. (2009) Increased indoleamine 2,3-dioxygenase (IDO) activity and elevated serum levels of tryptophan catabolites in patients with chronic kidney disease: a possible link between chronic inflammation and uraemic symptoms. Nephrol Dial Transplant 24: 1901–1908.JC SchefoldJP ZedenC. FotopoulouS. von HaehlingR. Pschowski2009Increased indoleamine 2,3-dioxygenase (IDO) activity and elevated serum levels of tryptophan catabolites in patients with chronic kidney disease: a possible link between chronic inflammation and uraemic symptoms.Nephrol Dial Transplant2419011908
  46. 46. Nelson S (1994) Role of granulocyte colony-stimulating factor in the immune response to acute bacterial infection in the nonneutropenic host: an overview. Clin Infect Dis 18: Suppl 2S197–204.S. Nelson1994Role of granulocyte colony-stimulating factor in the immune response to acute bacterial infection in the nonneutropenic host: an overview.Clin Infect Dis18Suppl 2S197204
  47. 47. Yoshida R, Imanishi J, Oku T, Kishida T, Hayaishi O (1981) Induction of pulmonary indoleamine 2,3-dioxygenase by interferon. Proc Natl Acad Sci U S A 78: 129–132.R. YoshidaJ. ImanishiT. OkuT. KishidaO. Hayaishi1981Induction of pulmonary indoleamine 2,3-dioxygenase by interferon.Proc Natl Acad Sci U S A78129132
  48. 48. Maes M, Meltzer HY, Scharpe S, Bosmans E, Suy E, et al. (1993) Relationships between lower plasma L-tryptophan levels and immune-inflammatory variables in depression. Psychiatry Res 49: 151–165.M. MaesHY MeltzerS. ScharpeE. BosmansE. Suy1993Relationships between lower plasma L-tryptophan levels and immune-inflammatory variables in depression.Psychiatry Res49151165
  49. 49. Bonaccorso S, Lin A, Song C, Verkerk R, Kenis G, et al. (1998) Serotonin-immune interactions in elderly volunteers and in patients with Alzheimer's disease (DAT): lower plasma tryptophan availability to the brain in the elderly and increased serum interleukin-6 in DAT. Aging (Milano) 10: 316–323.S. BonaccorsoA. LinC. SongR. VerkerkG. Kenis1998Serotonin-immune interactions in elderly volunteers and in patients with Alzheimer's disease (DAT): lower plasma tryptophan availability to the brain in the elderly and increased serum interleukin-6 in DAT.Aging (Milano)10316323
  50. 50. MacKenzie CR, Gonzalez RG, Kniep E, Roch S, Daubener W (1999) Cytokine mediated regulation of interferon-gamma-induced IDO activation. Adv Exp Med Biol 467: 533–539.CR MacKenzieRG GonzalezE. KniepS. RochW. Daubener1999Cytokine mediated regulation of interferon-gamma-induced IDO activation.Adv Exp Med Biol467533539
  51. 51. van der Sluijs KF, Nijhuis M, Levels JH, Florquin S, Mellor AL, et al. (2006) Influenza-induced expression of indoleamine 2,3-dioxygenase enhances interleukin-10 production and bacterial outgrowth during secondary pneumococcal pneumonia. J Infect Dis 193: 214–222.KF van der SluijsM. NijhuisJH LevelsS. FlorquinAL Mellor2006Influenza-induced expression of indoleamine 2,3-dioxygenase enhances interleukin-10 production and bacterial outgrowth during secondary pneumococcal pneumonia.J Infect Dis193214222
  52. 52. Maneechotesuwan K, Supawita S, Kasetsinsombat K, Wongkajornsilp A, Barnes PJ (2008) Sputum indoleamine-2, 3-dioxygenase activity is increased in asthmatic airways by using inhaled corticosteroids. J Allergy Clin Immunol 121: 43–50.K. ManeechotesuwanS. SupawitaK. KasetsinsombatA. WongkajornsilpPJ Barnes2008Sputum indoleamine-2, 3-dioxygenase activity is increased in asthmatic airways by using inhaled corticosteroids.J Allergy Clin Immunol1214350
  53. 53. Yanagawa Y, Iwabuchi K, Onoe K (2009) Co-operative action of interleukin-10 and interferon-gamma to regulate dendritic cell functions. Immunology 127: 345–353.Y. YanagawaK. IwabuchiK. Onoe2009Co-operative action of interleukin-10 and interferon-gamma to regulate dendritic cell functions.Immunology127345353
  54. 54. Hunsicker A, Kullich W, Weissenhofer W, Lorenz D, Petermann J, et al. (1997) Correlations between endotoxin, interferon-gamma, biopterin and serum phospholipase A2-activities during lethal gram negative sepsis in rats. Eur J Surg 163: 379–385.A. HunsickerW. KullichW. WeissenhoferD. LorenzJ. Petermann1997Correlations between endotoxin, interferon-gamma, biopterin and serum phospholipase A2-activities during lethal gram negative sepsis in rats.Eur J Surg163379385
  55. 55. Orabona C, Pallotta MT, Volpi C, Fallarino F, Vacca C, et al. (2008) SOCS3 drives proteasomal degradation of indoleamine 2,3-dioxygenase (IDO) and antagonizes IDO-dependent tolerogenesis. Proc Natl Acad Sci U S A 105: 20828–20833.C. OrabonaMT PallottaC. VolpiF. FallarinoC. Vacca2008SOCS3 drives proteasomal degradation of indoleamine 2,3-dioxygenase (IDO) and antagonizes IDO-dependent tolerogenesis.Proc Natl Acad Sci U S A1052082820833
  56. 56. van Wissen M, Snoek M, Smids B, Jansen HM, Lutter R (2002) IFN-gamma amplifies IL-6 and IL-8 responses by airway epithelial-like cells via indoleamine 2,3-dioxygenase. J Immunol 169: 7039–7044.M. van WissenM. SnoekB. SmidsHM JansenR. Lutter2002IFN-gamma amplifies IL-6 and IL-8 responses by airway epithelial-like cells via indoleamine 2,3-dioxygenase.J Immunol16970397044
  57. 57. Ulloa L, Ochani M, Yang H, Tanovic M, Halperin D, et al. (2002) Ethyl pyruvate prevents lethality in mice with established lethal sepsis and systemic inflammation. Proc Natl Acad Sci U S A 99: 12351–12356.L. UlloaM. OchaniH. YangM. TanovicD. Halperin2002Ethyl pyruvate prevents lethality in mice with established lethal sepsis and systemic inflammation.Proc Natl Acad Sci U S A991235112356
  58. 58. Jung ID, Lee MG, Chang JH, Lee JS, Jeong YI, et al. (2009) Blockade of indoleamine 2,3-dioxygenase protects mice against lipopolysaccharide-induced endotoxin shock. J Immunol 182: 3146–3154.ID JungMG LeeJH ChangJS LeeYI Jeong2009Blockade of indoleamine 2,3-dioxygenase protects mice against lipopolysaccharide-induced endotoxin shock.J Immunol18231463154
  59. 59. Ino K, Yamamoto E, Shibata K, Kajiyama H, Yoshida N, et al. (2008) Inverse correlation between tumoral indoleamine 2,3-dioxygenase expression and tumor-infiltrating lymphocytes in endometrial cancer: its association with disease progression and survival. Clin Cancer Res 14: 2310–2317.K. InoE. YamamotoK. ShibataH. KajiyamaN. Yoshida2008Inverse correlation between tumoral indoleamine 2,3-dioxygenase expression and tumor-infiltrating lymphocytes in endometrial cancer: its association with disease progression and survival.Clin Cancer Res1423102317
  60. 60. Le Tulzo Y, Pangault C, Gacouin A, Guilloux V, Tribut O, et al. (2002) Early circulating lymphocyte apoptosis in human septic shock is associated with poor outcome. Shock 18: 487–494.Y. Le TulzoC. PangaultA. GacouinV. GuillouxO. Tribut2002Early circulating lymphocyte apoptosis in human septic shock is associated with poor outcome.Shock18487494
  61. 61. Felmet KA, Hall MW, Clark RS, Jaffe R, Carcillo JA (2005) Prolonged lymphopenia, lymphoid depletion, and hypoprolactinemia in children with nosocomial sepsis and multiple organ failure. J Immunol 174: 3765–3772.KA FelmetMW HallRS ClarkR. JaffeJA Carcillo2005Prolonged lymphopenia, lymphoid depletion, and hypoprolactinemia in children with nosocomial sepsis and multiple organ failure.J Immunol17437653772
  62. 62. Hotchkiss RS, Tinsley KW, Swanson PE, Chang KC, Cobb JP, et al. (1999) Prevention of lymphocyte cell death in sepsis improves survival in mice. Proc Natl Acad Sci U S A 96: 14541–14546.RS HotchkissKW TinsleyPE SwansonKC ChangJP Cobb1999Prevention of lymphocyte cell death in sepsis improves survival in mice.Proc Natl Acad Sci U S A961454114546
  63. 63. Hotchkiss RS, Chang KC, Swanson PE, Tinsley KW, Hui JJ, et al. (2000) Caspase inhibitors improve survival in sepsis: a critical role of the lymphocyte. Nat Immunol 1: 496–501.RS HotchkissKC ChangPE SwansonKW TinsleyJJ Hui2000Caspase inhibitors improve survival in sepsis: a critical role of the lymphocyte.Nat Immunol1496501
  64. 64. Bommhardt U, Chang KC, Swanson PE, Wagner TH, Tinsley KW, et al. (2004) Akt decreases lymphocyte apoptosis and improves survival in sepsis. J Immunol 172: 7583–7591.U. BommhardtKC ChangPE SwansonTH WagnerKW Tinsley2004Akt decreases lymphocyte apoptosis and improves survival in sepsis.J Immunol17275837591
  65. 65. Schwulst SJ, Muenzer JT, Peck-Palmer OM, Chang KC, Davis CG, et al. (2008) Bim siRNA decreases lymphocyte apoptosis and improves survival in sepsis. Shock 30: 127–134.SJ SchwulstJT MuenzerOM Peck-PalmerKC ChangCG Davis2008Bim siRNA decreases lymphocyte apoptosis and improves survival in sepsis.Shock30127134
  66. 66. Fallarino F, Vacca C, Orabona C, Belladonna ML, Bianchi R, et al. (2002) Functional expression of indoleamine 2,3-dioxygenase by murine CD8 alpha(+) dendritic cells. Int Immunol 14: 65–68.F. FallarinoC. VaccaC. OrabonaML BelladonnaR. Bianchi2002Functional expression of indoleamine 2,3-dioxygenase by murine CD8 alpha(+) dendritic cells.Int Immunol146568
  67. 67. Odemuyiwa SO, Ghahary A, Li Y, Puttagunta L, Lee JE, et al. (2004) Cutting edge: human eosinophils regulate T cell subset selection through indoleamine 2,3-dioxygenase. J Immunol 173: 5909–5913.SO OdemuyiwaA. GhaharyY. LiL. PuttaguntaJE Lee2004Cutting edge: human eosinophils regulate T cell subset selection through indoleamine 2,3-dioxygenase.J Immunol17359095913
  68. 68. Lee GK, Park HJ, Macleod M, Chandler P, Munn DH, et al. (2002) Tryptophan deprivation sensitizes activated T cells to apoptosis prior to cell division. Immunology 107: 452–460.GK LeeHJ ParkM. MacleodP. ChandlerDH Munn2002Tryptophan deprivation sensitizes activated T cells to apoptosis prior to cell division.Immunology107452460
  69. 69. Forouzandeh F, Jalili RB, Germain M, Duronio V, Ghahary A (2008) Skin cells, but not T cells, are resistant to indoleamine 2, 3-dioxygenase (IDO) expressed by allogeneic fibroblasts. Wound Repair Regen 16: 379–387.F. ForouzandehRB JaliliM. GermainV. DuronioA. Ghahary2008Skin cells, but not T cells, are resistant to indoleamine 2, 3-dioxygenase (IDO) expressed by allogeneic fibroblasts.Wound Repair Regen16379387
  70. 70. Nohria A, Gerhard-Herman M, Creager MA, Hurley S, Mitra D, et al. (2006) Role of nitric oxide in the regulation of digital pulse volume amplitude in humans. J Appl Physiol 101: 545–548.A. NohriaM. Gerhard-HermanMA CreagerS. HurleyD. Mitra2006Role of nitric oxide in the regulation of digital pulse volume amplitude in humans.J Appl Physiol101545548
  71. 71. Barth MC, Ahluwalia N, Anderson TJ, Hardy GJ, Sinha S, et al. (2009) Kynurenic acid triggers firm arrest of leukocytes to vascular endothelium under flow conditions. J Biol Chem. MC BarthN. AhluwaliaTJ AndersonGJ HardyS. Sinha2009Kynurenic acid triggers firm arrest of leukocytes to vascular endothelium under flow conditions.J Biol Chem
  72. 72. Suzuki Y, Suda T, Furuhashi K, Suzuki M, Fujie M, et al. (2010) Increased serum kynurenine/tryptophan ratio correlates with disease progression in lung cancer. Lung Cancer 67: 361–365.Y. SuzukiT. SudaK. FuruhashiM. SuzukiM. Fujie2010Increased serum kynurenine/tryptophan ratio correlates with disease progression in lung cancer.Lung Cancer67361365
  73. 73. Torres MI, Lopez-Casado MA, Lorite P, Rios A (2007) Tryptophan metabolism and indoleamine 2,3-dioxygenase expression in coeliac disease. Clin Exp Immunol 148: 419–424.MI TorresMA Lopez-CasadoP. LoriteA. Rios2007Tryptophan metabolism and indoleamine 2,3-dioxygenase expression in coeliac disease.Clin Exp Immunol148419424
  74. 74. Kudo Y, Boyd CA, Sargent IL, Redman CW (2003) Decreased tryptophan catabolism by placental indoleamine 2,3-dioxygenase in preeclampsia. Am J Obstet Gynecol 188: 719–726.Y. KudoCA BoydIL SargentCW Redman2003Decreased tryptophan catabolism by placental indoleamine 2,3-dioxygenase in preeclampsia.Am J Obstet Gynecol188719726
  75. 75. Tattevin P, Monnier D, Tribut O, Dulong J, Bescher N, et al. (2010) Enhanced indoleamine 2,3-dioxygenase activity in patients with severe sepsis and septic shock. J Infect Dis 201: 956–966.P. TattevinD. MonnierO. TributJ. DulongN. Bescher2010Enhanced indoleamine 2,3-dioxygenase activity in patients with severe sepsis and septic shock.J Infect Dis201956966
  76. 76. Davis JS, Cheng AC, McMillan M, Anstey NM (2011) Sepsis in the tropical Northern Territory of Australia: high disease burden with disproportionate impact on Indigenous Australians. Med J Aust. JS DavisAC ChengM. McMillanNM Anstey2011Sepsis in the tropical Northern Territory of Australia: high disease burden with disproportionate impact on Indigenous Australians.Med J AustIn press. In press.
  77. 77. MacKenzie CR, Hadding U, Daubener W (1998) Interferon-gamma-induced activation of indoleamine 2,3-dioxygenase in cord blood monocyte-derived macrophages inhibits the growth of group B streptococci. J Infect Dis 178: 875–878.CR MacKenzieU. HaddingW. Daubener1998Interferon-gamma-induced activation of indoleamine 2,3-dioxygenase in cord blood monocyte-derived macrophages inhibits the growth of group B streptococci.J Infect Dis178875878
  78. 78. Merino E, Jensen RA, Yanofsky C (2008) Evolution of bacterial trp operons and their regulation. Curr Opin Microbiol 11: 78–86.E. MerinoRA JensenC. Yanofsky2008Evolution of bacterial trp operons and their regulation.Curr Opin Microbiol117886
  79. 79. Yanofsky C, Horn V, Gollnick P (1991) Physiological studies of tryptophan transport and tryptophanase operon induction in Escherichia coli. J Bacteriol 173: 6009–6017.C. YanofskyV. HornP. Gollnick1991Physiological studies of tryptophan transport and tryptophanase operon induction in Escherichia coli.J Bacteriol17360096017
  80. 80. Schefold JC, Zeden JP, Pschowski R, Hammoud B, Fotopoulou C, et al. (2010) Treatment with granulocyte-macrophage colony-stimulating factor is associated with reduced indoleamine 2,3-dioxygenase activity and kynurenine pathway catabolites in patients with severe sepsis and septic shock. Scand J Infect Dis 42: 164–171.JC SchefoldJP ZedenR. PschowskiB. HammoudC. Fotopoulou2010Treatment with granulocyte-macrophage colony-stimulating factor is associated with reduced indoleamine 2,3-dioxygenase activity and kynurenine pathway catabolites in patients with severe sepsis and septic shock.Scand J Infect Dis42164171
  81. 81. Lob S, Konigsrainer A, Rammensee HG, Opelz G, Terness P (2009) Inhibitors of indoleamine-2,3-dioxygenase for cancer therapy: can we see the wood for the trees? Nat Rev Cancer 9: 445–452.S. LobA. KonigsrainerHG RammenseeG. OpelzP. Terness2009Inhibitors of indoleamine-2,3-dioxygenase for cancer therapy: can we see the wood for the trees?Nat Rev Cancer9445452