Serum Kynurenine Concentrations Research Articles

Zinc Ameliorates Cadmium-Induced Immunotoxicity by Modulating Splenic Immunosuppressive Indoleamine 2,3-Dioxygenase Activity, Hematological Indices, and CD4+ T Cells via Inhibition of Cadmium Uptake in Male Wistar Rats.

Cadmium (Cd)-induced immunotoxicity has become a matter of public health concern owing to its prevalence in the environment consequently, great potential for human exposure. Zinc (Zn) has been known to possess antioxidant, anti-inflammatory, and immune-boosting properties. However, the ameliorating influence of Zn against Cd-induced immunotoxicity connecting the IDO pathway is lacking. Adult male Wistar rats were exposed to normal drinking water with no metal contaminants (group 1), group 2 received drinking water containing 200 μg/L of Cd, group 3 received drinking water containing 200 μg/L of Zn, and group 4 received Cd and Zn as above in drinking water for 42 days. Cd exposure alone significantly triggered the splenic oxidative-inflammatory stress, increased activities of immunosuppressive tryptophan 2,3-dioxygenase (TDO), indoleamine 2,3-dioxygenases (IDO) activities/protein expression, and decreased CD4+ T cell count, and a corresponding increase in the serum kynurenine concentration, as well as alterations in the hematological parameters and histologic structure when compared with the control (p < 0.05). Zn alone did not have any effect relative to the control group while co-exposure significantly (p < 0.05) assuaged the Cd-induced alterations in the studied parameters relative to the control. Cd-induced modifications in IDO 1 protein expression, IDO/TDO activities, oxidative-inflammatory stress, hematological parameters/CD4+ T cell, and histological structure in the spleen of rats within the time course of the investigation were prevented by Zn co-exposure via inhibition of Cd uptake.

Abatement of cyclophosphamide-induced splenic immunosuppressive indoleamine 2, 3-dioxygenase and altered hematological indices in Wister rats by dietary quercetin

The immunotoxicity mediated by cyclophosphamide (CYP) was earlier reported. Quercetin, due to its anti-oxidative/inflammatory properties elicits a plethora of health benefits. However, the influence of quercetin on the splenic/immunotoxicity linked with CYP-induced indoleamine 2,3-dioxygenase (IDO) is unavailable in the literature. We investigated the effects of quercetin on the splenic immunosuppressive IDO and hematological indices of immune response in rats. Animals were treated with CYP (100 mg/kg) alone or co-treated (CYP + quercetin [100 mg/kg + 50 mg/kg respectively]) at days 1, 3, 5, and 7. Results revealed that CYP treatment alone significantly provoked an oxidative-inflammatory response, increased serum kynurenine concentration, and concomitantly increased immunosuppressive IDO and tryptophan 2, 3-dioxygenase (TDO), in the spleen as well as altering hematological indices. Quercetin co-treatment enhanced activities of antioxidant enzymes, inhibited myeloperoxidase (MPO) activity, lowered levels of nitric oxide, interferon-Υ (IFN-Υ), and interleukin-6 (IL-6), and reduced kynurenine concentration as well as IDO/TDO activities. Quercetin co-treatment augmented white blood cell (WBC), CD4-T cells, and other hematological indices of the immune response. In conclusion, quercetin prevented CYP-induced alterations in immune response in rats by lowering the activities of immunosuppressive IDO and TDO, inhibiting oxidative-inflammatory stress, diminution of kynurenine concentrations, and augmenting hematological parameters.

T cell fat catabolism: A novel target for kynurenine?

T cell fat catabolism: A novel target for kynurenine?

Role of Bifidobacterium spp. intake in improving depressive mood and well-being and its link to kynurenine blood level: an interventional study.

Evidence for the contribution of the brain-gut-microbiota axis to the depression pathophysiology is increasing nowadays. Disturbed gut microbiota equilibrium along with bad dietary habits both lead to kynurenine pathway abnormalities contributing to the depression pathophysiology. In this respect, many studies are found but the interventional clinical trials are limited. The present interventional study aims to evaluate the impact of Bifidobacterium spp. supplementation together with improving dietary intake on depressive mood and well-being and their correlation with kynurenine blood level in adult Egyptian healthy volunteers. A number of 98 healthy female volunteers with a mean age of 46.96 ± 1.82 years were selected and enrolled in this study. They were given yogurt enriched with Bifidobacterium spp. daily for eight weeks. Clinical examination as well as questionnaires for the evaluation of psychological well-being and depression were done at base line and after eight weeks of intervention. Fasting blood samples and stool samples were collected from all subjects at baseline and eight weeks after the intervention for the investigation of serum kynurenine concentration, blood hemoglobin, serum transaminases (ALT & AST) serum urea and creatinine as well as fecal Bifidobacterium count. Data revealed that both depression and well-being showed highly significant improvement combined with significant drop in kynurenine blood level after intervention. Also, a significant rise in fecal Bifidobacterium count and a significant improvement in hemoglobin level and activity of liver enzymes were recorded. After intervention, a significant negative correlation was recorded between depression and fecal Bifidobacterium count as well as between serum kynurenine level, and well-being. Bifidobacterium spp. supplementation combined with improvement in dietary intake resulted in improvement of depressive mood and well-being and reduced kynurenine blood level.

Vitamin D supplementation ameliorates severity of generalized anxiety disorder (GAD).

This study investigated the effects of vitamin D supplementation on Generalized Anxiety Disorder (GAD) clinical symptoms and neurochemical biomarkers including serotonin, neopterin and kynurenine. Thirty male and female patients diagnosed with GAD and had vitamin D deficiency were recruited from the psychiatric clinic at King Abdulaziz University Hospital and divided into two groups; one group of patients (n = 15) received standard of care (SOC) plus 50,000IU vitamin D (once/week) for 3months, while the other group (n = 15) received SOC alone. Biochemical parameters including serum vitamin D, serotonin, neopterin and kynurenine were measured for all patients enrolled in the trial. In addition, the Generalized Anxiety Disorder 7-item (GAD-7) scale was used to measure the severity of GAD symptoms in both vitamin D treated- and untreated-patients. Significant improvements in GAD scores were observed in the vitamin D-treated group compared to the group that did not receive vitamin D. In addition, serum serotonin concentrations were significantly increased while serum neopterin were significantly decreased in vitamin D-treated vs. untreated patients. In contrast, no significant differences were found in serum kynurenine concentrations at the end of the study period between the two groups. No changes either in GAD-7 scores or in any of the biochemical measurements were observed in the group that received only SOC after 3months. Vitamin D supplementation was effective in ameliorating the severity of GAD symptoms by increasing serotonin concentrations and decreasing the levels of the inflammatory biomarker neopterin in GAD patients.

Correlation between kynurenine metabolites and postpartum depression

To explore the correlation between kynurenine (KYN) metabolites and postpartum depression (PPD), and to provide new possible explanation for the pathogenesis of postpartum depression (PPD). Methods: A total of 726 Chinese women, who received cesarean section, were enrolled in this study. PPD was diagnosed with an Edinburgh Postnatal Depression Scale (EPDS) score ≥13. Twenty-four women with PPD and 48 matched women without PPD were randomly selected. The perinatal serum concentrations of KYN, quinolinic acid (QUIN) and kynurenic acid (KYNA) were measured. Subsequently, the puerperants were compared for the differences in the serum concentrations of KYN, QUIN and KYNA at the end of term, day 1 and day 3 after cesarean section, respectively. Results: The incidence of PPD was 7.99%. Of clinical characteristics, pressure during pregnancy was significantly different between subjects with or without PPD (P<0.01). Patients with PPD showed significantly increased serum KYN concentration (P<0.05) at the end of term, increased serum QUIN concentration (P<0.05) and decreased KYNA concentration (P<0.05) on the third day after cesarean section as compared with the control women. Furthermore, the KYNA/QUIN ratio was significantly higher in patients with PPD as compared to the control women on the third day after cesarean section (P<0.01). Conclusion: The contribution of alterations in plasma levels of KYN, QUIN and KYNA is closely related with the incidence of PPD, and correction of KYNA/QUIN ratio could be a new strategy for the prevention and treatment of postpartum depressive symptoms.

Tryptophan metabolism and immunogenetics in major depression: A role for interferon-γ gene

The tryptophan metabolism and immune activation play a role in pathophysiology of major depressive disorders. The pro-inflammatory cytokine interferon-γ transcriptionally induces the indoleamine 2,3-dioxygenase enzyme that degrades the tryptophan and thus induces serotonin depletion. The polymorphism of certain cytokine genes was reported to be associated with major depression. We investigated the association between interferon-γ (IFNγ) gene CA repeat polymorphism, the profile of serotonin and tryptophan pathway metabolites and clinical parameters in 125 depressed patients and 93 healthy controls. Compared to controls, serum tryptophan and 5-hydroxyindoleacetic acid (5HIAA) concentrations in the patients were significantly lower and serum kynurenine concentrations were significantly higher at baseline (p<0.0001). The presence of IFNγ CA repeat allele 2 homozygous has significant association with higher kynurenine concentrations in controls (F=4.47, p=0.038) as well as in patients (F=3.79, p=0.045). The existence of interferon-γ CA repeat allele 2 (homo- or heterozygous) showed significant association with increase of tryptophan breakdown over time during the study period (F=6.0, p=0.019). The results indicated the association between IFNγ CA repeat allele 2, tryptophan metabolism and the effect of medication.

Association of enhanced activity of indoleamine 2,3-dioxygenase in dendritic cells with the induction of regulatory T cells in chronic hepatitis C infection

Altered functions of dendritic cells (DCs) and/or increases of regulatory T cells (Tregs) are involved in the pathogenesis of chronic hepatitis C virus (HCV) infection. A tryptophan-catabolizing enzyme, indoleamine 2,3-dioxygenase (IDO), is reported to be an inducer of immune tolerance. Our aim was to clarify whether or not IDO is activated in chronic hepatitis C patients and its role in immune responses. This study enrolled 176 patients with chronic HCV infection and 37 healthy volunteers. Serum kynurenine concentration was evaluated by high-performance liquid chromatography, and its correlation with clinical parameters was examined. Monocyte-derived DCs were prepared from the subjects and subsequently stimulated with a combination of lipopolysaccharide and interferon-gamma to induce functional IDO (defined as IDO-DCs). The phenotypes, kynurenine or cytokine production, and T-cell responses with IDO-DCs were compared between the patients and healthy volunteers. The serum kynurenine level in the patients was significantly higher than that in the healthy volunteers, and the level of serum kynurenine was positively correlated with the histological activity or fibrosis score. IDO activity in IDO-DCs from the patients was significantly higher than that in IDO-DCs from the volunteers. Furthermore, IDO-DCs from the patients induced more Tregs in vitro compared with those from the volunteers, and the frequency of induced Tregs by IDO-DCs was decreased with an IDO-specific inhibitor. Systemic IDO activity is enhanced in chronic hepatitis C patients in correlation with the degree of liver inflammation and fibrosis. In response to inflammatory stimuli, DCs from the patients tend to induce Tregs, with some of this action being dependent on IDO.

Indoleamine 2,3-dioxygenase expression and serum kynurenine concentrations in patients with diffuse large B-cell lymphoma

We have recently been able to clarify the utility of either serum l-kynurenine or tissue indoleamine 2,3-dioxygenase (IDO) expression as a prognostic factor for patients with diffuse large B-cell l...

Serum Tryptophan and Kynurenine Concentrations as Parameters for Indoleamine 2,3-Dioxygenase Activity in Patients With Endometrial, Ovarian, and Vulvar Cancer

Indoleamine 2,3-dioxygenase (IDO) suppresses the function of T-lymphocytes and is involved in immune escape of cancers. Indoleamine 2,3-dioxygenase catalyzes the initial rate-limiting step in the degradation of the essential amino acid tryptophan. In this study, we investigated cancer-induced IDO activity in sera of endometrial, ovarian, and vulvar cancer patients. Concentrations of tryptophan and kynurenine were determined in pretreatment serum samples of patients with endometrial (n = 41), ovarian (n = 28), and vulvar cancer (n = 40) and compared to 19 healthy female controls. In serum of a subgroup of endometrial (n = 22), ovarian (n = 21), and vulvar (n = 21) cancer patients, tryptophan, kynurenine, and the kynurenine-to-tryptophan ratio (kyn/trp) were determined at different time points: preoperative, at clinical remission, and at the time of diagnosis of recurrent disease. Analyses were performed by an automated online solid-phase extraction-liquid chromatographic-tandem mass spectrometric method. Indoleamine 2,3-dioxygenase activity was estimated by calculating the kyn/trp ratio. Kynurenine concentrations and the kyn/trp ratio were higher in preoperative serum of endometrial, ovarian, and vulvar cancer patients compared to controls (all: P < 0.001). Preoperative serum of ovarian cancer patients contained higher kynurenine concentrations (median, 2.53 μM; interquartile range [IQR], 1.72-4.29 μM) and a higher kyn/trp ratio (median, 39.3 μmol/mmol; IQR, 26.5-61.7 μmol/mmol) compared to serum collected at clinical remission (median, 2.02 μM; IQR, 1.68-2.72 μM, P = 0.035; and median, 29.9 μmol/mmol; IQR, 23.4-38.9 μmol/mmol, P = 0.005, respectively). Patients with endometrial, ovarian, and vulvar cancer have increased tryptophan degradation compared to controls resulting in higher serum kynurenine concentrations and a higher kyn/trp ratio. Our results suggest that IDO-induced immune escape may play an important role in these gynecologic cancers.

Pteridine Pathway in Patients with Degenerative Diseases During Short Time Treatment with Low Dose of Meloxicam, as a Non-steroidal Anti-inflammatory Drug

Abstract The profiles of unconjugated pteridines such as neopterin and biopterin and of tryptophan metabolism change in many pathologic conditions such as rheumatoid arthritis, malignancies and autoimmune diseases and are related to the release of pro-inflammatory cytokines. However, studies on potential effects of drugs are very limited. This study investigates whether meloxicam, a non-steroidal anti-inflammatory drug, may cause any alteration of the pteridine pathway and tryptophan metabolism in 22 patients who admitted to the Physical and Rehabilitation Medicine outpatient clinic in the Hacettepe University Hospital and suffering from various musculoskeletal pain conditions without systemic inflammation. Urine concentrations of neopterin, biopterin and xanthopterin, and serum concentrations of neopterin, tryptophan, and kynurenine, and the activity of dihydropteridine reductase were measured at the beginning of the therapy and after a 15 days treatment with meloxicam. Average urine concentrations (± S.E.M.) of pterins before therapy (neopterin: 263 ± 15.6 μmol/mol creatinine, biopterin: 72.4 ± 13.4 μmol/mol creatinine, and xanthopterin: 675 ± 93.0 μmol/mol creatinine) were not changed during meloxicam therapy (neopterin: 230 ± 30.7 μmol/mol creatinine = 88% of baseline, biopterin 115 ± 26.5 μmol /mol creatinine = 159% of baseline, and xanthopterin 684 ± 88.0 μmol/mol creatinine = 101% of baseline; all differences not significant). The activity of dihydropteridine reductase was 6.02 ± 0.21 nmol/cytochrome C reduced/min/5 mm disc before and 6.28 ± 0.18 nmol/cytochrome C reduced/min/5 mm after treatment (= 104% of baseline; p = 0.088). Serum concentrations of neopterin 6.04 ± 0.33 nmol/L before treatment increased to 6.89 ± 0.48 nmol/L after treatment (= 114% of baseline; p &lt;0.05, paired rank test). Likewise serum kynurenine concentrations increased from 1.52 ± 0.13 μmol/L to 1.87 ± 0.14 μmol/L after treatment (= 123% of baseline; p &lt;0.01). There was a significant correlation between neopterin and kynurenine concentrations which corresponds with their common background of production, namely immune activation. However, also the mean tryptophan concentration in pretreatment samples 51.4 ± 3.34 increased to 59.3 ± 3.34 μmol/L post-treatment (= 115% of baseline; p &lt;0.05). The change of kyn/trp was minor (at baseline: 30.4 ± 2.01, post-treatment: 32.2 ± 2.47 μmol/mmol; = 106% of baseline, not significant). Our findings show an influence of meloxicam treatment on neopterin and tryptophan metabolism in patients. However, significant differences were only found in serum but not in urine of patients. In serum, all marker concentrations increased including tryptophan and kynurenine.

Relationship between serum kynurenine concentration and exercise performance

Abstract We have hypothesized that a close correlation exists between tryptophan metabolism, exercise performance and mood. Before and after a 20-km run, a POMS test and serum l -kynurenine determination were performed. Serum l -kynurenine concentration was negatively correlated with running distance. After running, scores for Vigor and serum l -kynurenine concentration were correlated (r = 0.556); subjects with higher l -kynurenine concentrations tended to have higher scores for Vigor. In this study, we attempted to confirm this hypothesis. The present results suggest a close correlation between tryptophan metabolism, exercise performance and mood.

Altered Tryptophan Metabolism in FIV‐Positive Cats

Background:Feline immunodeficiency virus (FIV) is analogous to human immunodeficiency virus, the causative agent of human acquired immunodeficiency syndrome (AIDS). In AIDS patients, a progressive reduction in serum tryptophan concentration occurs because of activation of an inducible tryptophan degradation pathway mediated by elevated Λ‐interferon production.Hypothesis:Cats infected with FIV have increased tryptophan catabolism evidenced by reduced circulating concentrations of tryptophan and increased concentrations of the tryptophan catabolite kynurenine.Animals:Convenience sample of 235 cats submitted for diagnostic FIV serology (115 FIV‐negative and 120 FIV‐positive cats).Methods:Retrospective, cross‐sectional study. Serum was assayed for tryptophan and kynurenine using a high performance liquid chromatography assay with fluorescence and ultraviolet detection, respectively.Results:Tryptophan and kynurenine concentrations were log‐normally distributed. Geometric mean concentrations were: tryptophan: FIV‐positive 30.6 μM (95% CI: 26.8–34.8 μM), FIV‐negative 48.9 μM (95% CI: 43.6–54.9 μM) (P &lt; .001); kynurenine: FIV‐positive 22.7 μM (95% CI: 25.5–10.9 μM), FIV‐negative 9.9 μM (95% CI: 20.3–9.03 μM) (P &lt; .001). The ratio of kynurenine to tryptophan was: FIV‐positive 4.93 (95% CI: 5.62–4.32), FIV‐negative 1.34 (95% CI: 1.53–1.17) (P &lt; .0001).Conclusions and Clinical Importance: Serum tryptophan concentration was significantly lower and serum kynurenine concentration was significantly higher in FIV‐positive cats. The kynurenine: tryptophan ratio was &gt;3‐fold higher in FIV‐positive animals, indicating increased tryptophan catabolism in this group. Dietary or pharmacologic intervention to support serum tryptophan concentrations has been shown to be clinically useful in humans with AIDS and might be applicable to cats with FIV infection.

Altered Tryptophan Metabolism in FIV-Positive Cats

Feline immunodeficiency virus (FIV) is analogous to human immunodeficiency virus, the causative agent of human acquired immunodeficiency syndrome (AIDS). In AIDS patients, a progressive reduction in serum tryptophan concentration occurs because of activation of an inducible tryptophan degradation pathway mediated by elevated lamda-interferon production. Cats infected with FIV have increased tryptophan catabolism evidenced by reduced circulating concentrations of tryptophan and increased concentrations of the tryptophan catabolite kynurenine. Convenience sample of 235 cats submitted for diagnostic FIV serology (115 FIV-negative and 120 FIV-positive cats). Retrospective, cross-sectional study. Serum was assayed for tryptophan and kynurenine using a high performance liquid chromatography assay with fluorescence and ultraviolet detection, respectively. Tryptophan and kynurenine concentrations were log-normally distributed. Geometric mean concentrations were: tryptophan: FIV-positive 30.6 microM (95% CI: 26.8 34.8 microM), FIV-negative 48.9 [microM (95% CI: 43.6-54.9 microM) (P < .001); kynurenine: FIV-positive 22.7 microM (95% CI: 25.5-10.9 microM), FIV-negative 9.9 microM (95% CI: 20.3-9.03 microM) (P < .001). The ratio of kynurenine to tryptophan was: FIV-positive 4.93 (95% CI: 5.62-4.32), FIV-negative 1.34 (95% CI: 1.53 1.17) (P < .0001). Serum tryptophan concentration was significantly lower and serum kynurenine concentration was significantly higher in FIV-positive cats. The kynurenine: tryptophan ratio was >3-fold higher in FIV-positive animals, indicating increased tryptophan catabolism in this group. Dietary or pharmacologic intervention to support serum tryptophan concentrations has been shown to be clinically useful in humans with AIDS and might be applicable to cats with FIV infection.

Mechanisms dependent on tryptophan catabolism regulate immune responses in primary Sjögren's syndrome

To investigate the possible role of tryptophan metabolism in immune regulation of primary Sjögren's syndrome (pSS) the serum concentrations of tryptophan and its metabolite kynurenine were measured by reverse-phase high-performance liquid chromatography (HPLC) in 103 patients with pSS, 56 patients with sicca symptoms and 309 healthy blood donors. The kynurenine per tryptophan ratio (kyn/trp), which reflects the activity of the indoleamine-pyrrole 2,3-dioxygenase (IDO) enzyme involved in tryptophan catabolism, was calculated. Both female and male patients with pSS had significantly higher serum kynurenine concentrations and kyn/trp than subjects with sicca symptoms or healthy blood donors. The median (quartile range) concentration of kynurenine in female patients with pSS was 2.41 micromol/l (1.86-3.26) compared with 1.85 micromol/l (1.58-2.38, P < 0.0001) in subjects with sicca symptoms and 1.96 micromol/l (1.65-2.27, P < 0.0001) in healthy blood donors. Their kyn/trp x 1000 was 34.0 (25.1-44.3) compared with 25.3 (21.1-31.5, P < 0.0001) in subjects with sicca symptoms and 24.3 (21.0-28.9, P < 0.0001) in healthy blood donors. Female pSS patients with high IDO activity (kyn/trp x 1000 > or = 34.0) had significantly higher ESR, serum C-reactive protein, serum IgA and serum beta-2 microglobulin concentrations as well as higher serum creatinine levels, and they had positive antinuclear antibodies more frequently and presented with more American-European consensus group criteria than those with low IDO activity (kyn/trp x 1000 < 34.0). These data suggest that mechanisms dependent on tryptophan catabolism regulate immune responses in pSS. Tryptophan degradation is enhanced in patients with pSS, and high IDO activity is associated with severity of pSS.

Tryptophan metabolism was accelerated by exercise in rat.

We have already reported that exercise activates kynurenine pathway. But, the mechanism for this activation by exercise is still unclear. Kynurenine is metabolized to NAD, which is an essential factor for energy metabolism. In this study, exercise on treadmill was loaded to rats until all-out and tryptophan metabolites and tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) activities were determined in the blood, livers, and macrophages, respectively, in the exercise-loaded rats. The mean values of serum tryptophan concentration decreased from 92.6 +/- 6.0 nmol/ml to 52.4 +/- 10.2 nmol/ml (p<0.05) just after treadmill load. The serum kynurenine concentration had increased from 2.06 +/- 0.25 nmol/ml to 3.08 +/- 0.62 nmol/ml (p<0.005). And whole blood NAD concentration increased from 68.8 +/- 14.6 nmol/ml to 77.9 +/- 19.1 nmol/ml (p<0.005). These results showed that exercise activated the kynurenine pathway of tryptophan metabolism and made NAD which will be concerned with energy metabolism in mitochondria. Tryptophan-NAD pathway was initiated by cleavage of indole ring of tryptophan by TDO in the liver and IDO in many organs. We had also found that the exercise increase IDO activity of macrophages, but not TDO activity.

Increased Depressive Ratings in Patients With Hepatitis C Receiving Interferon-α–Based Immunotherapy Are Related to Interferon-α–Induced Changes in the Serotonergic System

There is now evidence that repeated administration of interferon-alpha (IFN-alpha) to patients with chronic active hepatitis and cancers induces depressive symptoms. There is also evidence that induction of the cytokine network modulates the serotonergic system and that major depression is related to activation of the cytokine network and disturbances in the serotonergic metabolism. The aims of this study were to examine the effects of IFN-alpha-based immunotherapy on the development of depressive symptoms in relation to its effects on plasma tryptophan and kynurenine and serum serotonin (5-HT). Eighteen patients affected by chronic active hepatitis C were treated with IFN-alpha (3-6 million units subcutaneously three to six times a week for 6 months) and had measurements of the previous parameters before starting immunotherapy and 2, 4, 16, and 24 weeks later. Severity of depression and anxiety were measured with the Montgomery-Asberg Depression Rating Scale (MADRS) and the Hamilton Rating Scale for Anxiety (HAM-A) scale, respectively. Immunochemotherapy with IFN-alpha (1) significantly increased the MADRS and HAM-A scores and serum kynurenine concentrations and (2) significantly reduced plasma tryptophan and serum 5-HT concentrations. IFN-alpha-based immunotherapy significantly increased the kynurenine per tryptophan quotient, which estimates the activity of indoleamine 2,3-dioxygenase, the major tryptophan-catabolizing enzyme, which is induced by IFNs. There are significant relationships between the IFN-alpha-induced changes in the MADRS score and serum kynurenine (positive) and 5-HT (negative) concentrations. Immunotherapy with IFN-alpha significantly increases the severity of depressive symptoms. The latter is related to changes in the serotonergic system, such as depletion of serum 5-HT and induction of the catabolism of tryptophan to kynurenine. It is suggested that the IFN-alpha-induced changes in the serotonergic turnover could play a role in the development of IFN-alpha-induced depressive symptoms.

Kynurenine concentration of serum was increased by exercise.

Kynurenine pathway of tryptophan makes a lot of physiological active substances, such as quinolinate, NAD and so on, suggesting that kynurenine itself may play a very important role physiologically. Therefore, we examined the influence of exercise on serum kynurenine concentration. At first, we assayed kynurenine concentration of students (n = 13) who took part in a rugby camp for three days. The mean value of kynurenine concentration of before and after training were 1.362 +/- 0.306 microM and 1.725 +/- 0.511 microM respectively. These data means that severe exercise rise the serum kynurenine concentration. Then we tried to examine the relationship between the level of exercise and serum kynurenine concentration. Serum kynurenine concentration had significantly increased immediately after the exercise from 1.869 +/- 0.285 microM to 2.138 +/- 0.248 microM of 24 hours later by loading of 65% heart rate max exercise for each subject. These results suggested that at least the severe exercise affect on the tryptophan metabolism. We will discuss the change of serum kynurenine concentration by another sports such as soccer game and 20 km run.