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Concentrations of neopterin, a product of interferon-g-stimulated human monocytes/macrophages, allow to monitor activated cellular immune response and to estimate oxidative stress elicited thereby. Interferon-g stimulates also tryptophan degradation in various cells to produce kynurenine, the kynurenine to tryptophan ratio (kyn/trp) indicating immune activation. Homocysteine accumulates during deficiency of vitamins folate, B12 and B6. We examined serum concentrations of neopterin (ELISA), tryptophan, kynurenine, homocysteine (all HPLC), folate and B12 (all RIA) in 33 healthy individuals aged 26-93y (mean 64.8y) without signs of any disease. Comparing 3 age groups of equal size (26y-65y, 66y-70y, 71 y-93y), concentrations of neopterin (p

A fast responding fiber-optic microsensor for sensing pCO2 in marine sediments with high spatial resolution is presented. The tip diameter varies typically between 20 and 50 μm. In order to make the pH-indicator ¶8-hydroxypyrene-1,3,6-trisulfonate soluble in the ethyl cellulose matrix, it was lipophilized with tetraoctylammonium as the counterion [HPTS-(TOA)4]. The microsensor was tuned to sense very low levels of dissolved carbon dioxide which are typically present in marine systems. The detection limit is 0.04 hPa pCO2 which corresponds to 60 ppb CO2 of dissolved carbon dioxide. A soluble Teflon derivative with an extraordinarily high gas permeability was chosen as a protective coating to eliminate interferences by ionic species like chloride or pH. Response times of less than 1 min were observed. The performance of the new microsensor is described with respect to reproducibility of the calibration curves, dynamic range, temperature behavior, long term stability and storage stability. The effect of hydrogen sulfide as an interferent, which is frequently present in anaerobic sediment layers, was studied in detail. [ABSTRACT FROM AUTHOR]

Immune system activation and inflammation accompanies immune dysfunction in trauma and sepsis patients. Tryptophan degradation via the kynurenine pathway by the cytokine-inducible enzyme indoleamine 2,3-dioxygenase (IDO) could contribute to the deficient responsiveness of immunocompetent cells. Activated IDO in patients after trauma and with sepsis is indicated by an increased kynurenine to tryptophan ratio (kyn/trp), which was found to be associated with poor outcome of patients. In this study, tryptophan and kynurenine concentrations in 18 patients post trauma or with sepsis during 12-14 days of follow up (up to 84 specimens were available) were compared to concentrations of neopterin and cytokines tumor necrosis factor-α (TNF-α) and interleukin- 6 (IL-6) and the in vitro response of lipopolysaccharide-stimulated monocytes. Compared to healthy controls, average kyn/trp and kynurenine, TNF-α, IL-6 and neopterin concentrations were increased in patients, and tryptophan concentrations were decreased. During follow-up, only kyn/trp, kynurenine and neopterin concentrations (all p

Extract of traditional Tibetan herbal remedy Padma 28 revealed suppressive effects on neopterin production and tryptophan degradation in mitogen-stimulated peripheral blood mononuclear cells (PBMC). One of the questions was to asses the robustness of the Tibetan way of formulating herbal multicomponent medicines. Can small changes affect the effectiveness of the formula? In this study, effect of a derivative multicomponent mixture was investigated in stimulated and unstimulated human PBMC in vitro. Neopterin production and tryptophan degradation were measured in supernatants of PBMC in the presence or absence of mitogens phytohacmagglutinin and concanavalin A. Stimulation of PBMC induced neopterin formation and tryptophan degradation, and the herbal multicomponent mixture inhibited both immunobiochemical effects in a dose-dependent way. Higher concentrations were more effective and were able to completely block the pathways induccd upon mitogenic stimulation. When comparing the results obtained with those observed earlier using Padma 28, there was no obvious difference between the two different preparations. Data allow to conclude that Padma 28 and its modified version is equally able to suppress immunobiological effects in stimulated PBMC.

Population-based studies suggest moderate and regular consumption of alcoholic beverages and especially of red wine to reduce morbidity and mortality from coronary heart disease. These beverages may interfere with immune activation cascades crucial in the pathogenesis of coronary heart diseases. Neopterin concentrations in human body tluids were found to increase in the course of coronary heart disease indicating the activity of the atherogenetic process. In this study, human peripheral blood mononuclear cells (PBMC) stimulated with mitogens phytohaemagglutinin and concanavalin A were exposed to red and white wines, to ethanol and to grape juice as a non-alcoholic control in vitro. Neopterin production and tryptophan degradation were measured in supcrnalants. Both biochemical effects are induced by Th 1-type cytokine interferon-y and allow monitoring of immune actnation. In stimulated PBMC increased production of neopterin and degradation of tryptophan was observed Red and white wines, as well as grape juice inhibited these stimulation-induced effects, higher concentrations being more cffective. Ethanol had comparably small if any effect, Red and white wines as well as grape juice down regulate cytokine-mediated effects in PBMC. Most likely, antioxidant ingredients of wine and grape juice such as resveratrol are capable of interfering with immunologic pathways which appear to be of relevance, e g.. in the pathogenesis of cardiovascular disease.

Human monocyte-derived macrophages and dendritic cells produce increased amounts of neopterin derivatives upon stimulation with interferon-γ (IFN-γ). In parallel, such stimulated cells release a record of oxidizing specics as part of their cytocidal repertoire. Production of reactive oxygen species by stimulated immunocompetent cells may be the reason for the depletion of antioxidant vitamins and the development of oxidative stress during diseases with stimulated immune system. Noteworthy also neopterin derivatives are able to interfere with reactive oxygen, chlorine, and nitrogen species, and neopterin itself could contribute to oxidative stress. In vivo, neopterin concentrations thus allow not only to monitor cell-mediated immune response, they also allow to estimate the extent of oxidative stress which emerges during immune response. In certain diseases associations between higher neopterin levels and markers of oxidative stress have been reported. In neurodegenerative diseases, neopterin concentrations in scrum and cerebrospinal fluid also correlate with the cognitive decline in patients. In this studv we compared serum concentrations of neopterin with serum concentrations of peroxides and homocysteine in patients with various forms of dementia and in 5 healthy elderly controls. In patients of either form of dementia serum concentrations of peroxides and neopterin were increased compared to controls. There existed a positive correlation between age and concentrations of peroxides, neopterin and homocysteine. The data further supportile view that increased neopterin concentrations are associated with oxidative stress which could underlie c¡r increased demand of antioxidants in neurodegenerative disorders. It appears important that such changes can h> detected in the blood of patients with dementia, albeit its pathogenesis is considered to be confined to the brain The results further suggest that aging is associated with immune system activation which may lead to the increased production of peroxides.

Objectives: An HPLC method was developed to quantify serum concentrations of phenylalanine and tyrosine simultaneously using fluorescence detection without derivatization., Methods: Serum protein is precipitated with trichloroacetic acid, 0.015mM dihydrogen-phosphate solution is used for separation on reversed-phase C18 material, and acetonitrile is avoided. Both amino acids are monitored utilizing their natural fluorescence at 210nm excitation and 302nm emission wavelengths., Results: One analytical run is completed within 7min. Lower detection limit for Phe and Tyr is 0.3μM. Comparison of the new method with a classical HPLC method for total amino acids and using UV-absorption detection reveals a highly significant relationship for Phe and Tyr., Conclusion: The new HPLC method allows rapid and very sensitive measurement of phenylalanine and tyrosine concentrations., (© 2013. Published by Elsevier Inc. on behalf of The Canadian Society of Clinical Chemists. All rights reserved.)

Tryptophan-degrading enzyme indoleamine 2,3-dioxygenase (IDO) represents an antimicrobial and antitumoral immune effector mechanism, but IDO also suppresses T-cell responses and thus can cause immune system failure. Therefore, IDO was proposed as an immunoescape mechanism of tumor cells. Compared to healthy controls, accelerated tryptophan degradation was observed in the blood of 20 patients with ovarian carcinoma as is reflected by an increased kynurenine to tryptophan ratio (kyn/trp) which allows an estimate of IDO activity. Higher FIGO stage but not tumor grading was associated with a higher rate of tryptophan degradation. Kyn/trp correlated strongly with concentrations of cytokine IL-6, of soluble interleukin-2 receptor-α and 75 kDa TNF-α receptor and of the macrophage marker neopterin (all p<0.001 or p<0.01) but not with TNF-α. Findings further supports the concept that increased IDO activity in ovarian cancer patients relates to immune activation pathways. Accordingly, accelerated tryptophan degradation appears to represent an immune escape mechanism. However IDO activity is not necessarily a spontaneous activity of ovarian cancer cells rather it is elicited by the activated immune system although an additional spontaneous activity of tumor cells cannot be ruled out., (Copyright © 2010 Elsevier GmbH. All rights reserved.)

Moderate hyperhomocysteinemia is a well-established coronary risk factor that develops when dietary supply with folate and/or vitamin B(12) is inadequate. Recently, stimulated peripheral blood mononuclear cells were shown to produce homocysteine. Thus, the stimulated immune system may contribute to moderate hyperhomocysteinemia during certain diseases. Because multiple trauma and sepsis are accompanied by often strong inflammatory responses, we investigated whether hyperhomocysteinemia may develop in patients. Total homocysteine and cysteine concentrations were measured in 83 plasma specimens from 18 patients (14 men, 4 women; 15 posttrauma with sepsis and 3 with sepsis alone) every third day of follow-up. Finally results were compared with concentrations of cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-6, the immune activation marker neopterin and the extent of tryptophan degradation as indicated by the kynurenine-to-tryptophan ratio (kyn/trp). Compared with baseline, average total homocysteine (P < 0.05, d 4-d 10) and cysteine (P < 0.05, d 7-d 13) concentrations increased during follow-up of patients. However, only the increase of homocysteine was related to the survival status: total homocysteine was significantly higher in nonsurvivors (P < 0.05, d 4 and d 10) than in survivors, whereas cysteine concentrations increased in both subgroups. Homocysteine correlated with kyn/trp but not with neopterin concentrations. Increase of total homocysteine is common in patients after trauma with unfavorable outcome. Because all patients received standardized enteral nutrition after the end of hypodynamic shock, inconsistent vitamin supply is unlikely to be the reason for hyperhomocysteinemia in some of the patients; rather, it is associated with a stronger proinflammatory response. Certainly, the number of patients in our study is still small and results can only be regarded as preliminary.

Objective: Higher blood levels of the essential amino acid phenylalanine (phe) have been documented in patients with HIV-1 infection. They may relate to a diminished conversion of phe to tyrosine (tyr) by the enzyme phenylalanine-hydroxylase (PAH). PAH is rate-limiting in the biosynthesis of dopamine, and impaired PAH activity is reflected by an increased phe to tyr ratio (phe/tyr)., Methods: Plasma phe/tyr was measured in 107 patients with HIV-1 infection before and after 12 months of effective antiretroviral therapy (ART). Results were compared with CD4+ cell counts, HIV-1 RNA levels and concentrations of immune activation marker neopterin., Results: Before ART, phe/tyr was mean+/-S.D.: 0.99+/-0.57 micromol/micromol. Phe/tyr correlated significantly with plasma and urine neopterin concentrations (rs=0.434, and rs=0.392; both p<0.001) and less strongly with HIV-RNA levels (rs=0.173) and CD4+ counts (rs=-0.182, both p<0.05). After ART, phe/tyr dropped to 0.72+/-0.16 (=-27%; U=5.21, p=0.01) which was due to an average decline of -14% of phe concentrations from 73.1+/-34.0 micromol/L at baseline to 62.9+/-17.8 micromol/L after ART (U=2.51, p=0.01) and a concomitant increase of tyr concentrations (+13%, U=2.46, p=0.01). In parallel, significant reductions of plasma and urine neopterin concentrations were observed during ART., Conclusions: Increased phe/tyr is frequent in patients with HIV-1 infection and is related to immune activation. ART was found to decrease phe/tyr and this change could indicate and influence on PAH activity. Future studies might be able to show whether the decline of phe/tyr under ART may concur with the often improved neuropsychiatric status in treated patients., (2009 Elsevier Inc. All rights reserved.)

Immune system activation and inflammation accompanies immune dysfunction in trauma and sepsis patients. Immunodeficiency may develop in such patients as one consequence of an activated chronic pro-inflammatory response. According to recent data, degradation of L-tryptophan (TRP) via the kynurenine (KYN) pathway by the cytokine-inducible enzyme indoleamine 2,3-dioxygenase (IDO) could represent an important contributor to the deficient responsiveness of immunocompetent cells. Compared to healthy controls, patients post trauma or with sepsis had increasing KYN concentrations and KYN to TRP ratios (KYN/TRP) whereas TRP concentrations decreased. Likewise, concentrations of cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) and of immune activation marker neopterin increased in patients (all p < 0.001). Furthermore in patients KYN/TRP, KYN and neopterin concentrations were further increasing (all p < 0.001), whereas the changes of TRP, TNF-α and IL-6 concentrations were not significant. Compared to the survivors, the non-survivors had a higher concentration of KYN, neopterin, TNF-α and IL-6 as well as a higher KYN/TRP ratio. KYN/TRP correlated with neopterin (p < 0.001) and also with TNF-α (p < 0.01) and IL-6 concentrations (p < 0.05) and inversely with the in vitro response of stimulated monocytes. We conclude that increased TRP degradation in patients post trauma is closely associated with immune activation. Cytokines released during the pro-inflammatory response may induce the activity of IDO and thus accelerate TRP degradation. Thus, increased IDO activity most likely represents a result of host response to pro-inflammation in patients. Data support a possible role of inflammation-induced IDO in the diminished immunoresponsiveness in patients.

Immune dysfunction in trauma patients is associated with immune system activation and inflammation. The cytokine-inducible enzyme IDO (indoleamine 2,3-dioxygenase) initiates the degradation of the essential aromatic amino acid tryptophan via the kynurenine pathway and could contribute to deficient immune responsiveness. Activated IDO is indicated by an increased kyn/trp (kynurenine/tryptophan) ratio. The aim of the present study was to investigate whether tryptophan degradation is associated with outcome in patients post-trauma. Tryptophan and kynurenine concentrations were measured by HPLC in serum specimens of 15 patients post-trauma during 12-14 days of follow-up. Up to five samples within this observation period from each patient were included in this analysis, and a total a 69 samples were available. For further comparisons, concentrations of the immune activation marker neopterin were measured. Compared with healthy controls, the average kyn/trp ratio and kynurenine concentrations were increased in patients, whereas tryptophan concentrations were decreased. During follow-up, increased kyn/trp ratio and kynurenine concentrations (all P<0.001) were observed, whereas the changes in tryptophan concentrations were not significant. Non-survivors had higher kyn/trp ratios and kynurenine concentrations compared with survivors. The kyn/trp ratio correlated with neopterin concentrations (r(s)=0.590, P<0.001). In conclusion, these results imply that increased tryptophan degradation in patients is due to activated IDO, which most probably is a consequence of a host defence response. These findings support a possible role for IDO in the development of immunodeficiency and death in patients.

Increased blood concentrations of essential amino acid phenylalanine are common in patients with HIV infection, in trauma and sepsis and in patients with cancer. The reason for this phenomenon is still unclear. However, all these clinical conditions are known to be linked with inflammation and immune activation. Oxidative stress resulting from chronic immune activation and inflammation could impair activity of phenylalanine (4)-hydroxylase (PAH) and thus give rise to increased phenylalanine concentrations. We therefore examined in 20 patients with ovarian cancer a possible association of serum concentrations of phenylalanine and tyrosine with immune activation markers 75 kDa soluble tumor necrosis factor-alpha receptor (sTNF-R75) and neopterin, and of oxidative stress marker isoprostane-8. Phenylalanine concentrations were higher in patients with higher FIGO stage and correlated with concentrations of sTNF-R75 (rs=0.441) and neopterin (rs=0.346; both p<0.05). No such correlations existed for tyrosine levels. The phenylalanine to tyrosine ratio (phe/tyr), an estimate of PAH activity, correlated somewhat stronger with sTNF-R75 (rs=0.549; p<0.01) and neopterin (rs=0.497; p=0.01). Finally, phenylalanine concentrations correlated with isoprostane-8 concentrations (rs=0.450, p=0.02). Correlations of phenylalanine and phe/tyr with immune activation markers point to a potential role of inflammation and immune activation in the accumulation of phenylalanine. The relationship between oxidative stress marker isoprostane-8 and phenylalanine as well as sTNF-R75 concentrations suggests a link between reactive oxygen species formed during chronic immune activation and inflammation and the decline of PAH activity, which might underlie the increase of phe/tyr (248 words).

Intrathecal production of neopterin, a pteridine produced by interferon (IFN)-gamma-stimulated monocyte-derived macrophages, is associated with neurological disorders and infections. We investigated whether IFN-alpha/beta, IFN-gamma, or human immunodeficiency virus (HIV) induce neopterin production by human astroglioma cells. IFN-alpha/beta and IFN-gamma, but not HIV, induced neopterin. Interestingly, IFN-gamma, but not IFN-alpha/beta, increased expression and activity of the tryptophan-catabolizing enzyme indoleamine (2,3)-dioxygenase. In contrast, IFN-alpha/beta, but not IFN-gamma, reduced the uptake of three aromatic amino acids in U87MG and U138 astroglioma cells. Thus type I and type II IFN stimulate astrocyte-derived cells to produce neopterin and exert differential effects on amino acid metabolism.

Simultaneous fluorometric sensing of two analytes becomes possible using a modified dual lifetime referencing (m-DLR) method. In this scheme, two luminescent indicators are needed that have overlapping absorption and emission spectra but largely different decay times. They are excited by a single light source, and both emissions are measured simultaneously. In the frequency domain m-DLR method, the phase of the short-lived fluorescence of a first indicator is referenced against that of the long-lived luminescence of the second indicator. The analytical information is obtained by measurement of the phase shifts at two modulation frequencies. The method is demonstrated to work for the case of dually sensing oxygen and carbon dioxide. It benefits from simple instrumentation and optical setup. The approach is perceived to be of wide applicability. Examples include (1) analysis of two luminescent analytes, (2) analytical determinations that make use of two probes, and (3) sensing of two species such as carbon dioxide and oxygen (as demonstrated here), or oxygen and chlorophyll, provided the luminophores meet the condition of having largely different decay times and overlapping absorption and emission spectra.

Background: Activation of the tryptophan-degrading enzyme indoleamine (2,3)-dioxygenase was demonstrated to be critically involved in tolerance induction to prevent fetal rejection. Our study was designed to examine alterations of tryptophan and its catabolic product kynurenine in the postpartum period and to compare them to neopterin as an immunological marker., Methods: 95 healthy women delivering without complications provided blood during labour, and 2 and 4 days after birth. The blood samples were analysed for concentrations of tryptophan, kynurenine and neopterin. Women were asked to perform the Edinburgh Postnatal Depression Scale (EPDS) on days 2 and 4., Results: In women without blues symptoms (n=86) tryptophan concentrations increased within 2 days after birth, whereas they did not change in women with postpartum blues (n=9; 9.5%). The group difference reached statistical significance (p<0.05). The change of the kynurenine to tryptophan ratio (kyn/trp), which estimates the degree of tryptophan degradation, was also different between the two groups at days 0 and 2 (p<0.05). Neopterin concentrations decreased between days 2 and 4 (p<0.05), but there were no differences between the two groups., Limitations: Our study population had a low prevalence of postpartum blues symptoms., Conclusion: Low postpartal mood is associated with continuously low serum tryptophan after delivery due to an increased degradation to kynurenine, but is independent of the postpartal course of neopterin.

Decreased lymphocyte proliferation, lymphopenia, immunodepression, and opportunistic infections are common after major trauma. Early alimentation in these patients corrects lymphopenia, enhances immunity, and reduces the incidence of infections, but the underlying mechanisms are poorly understood. Tryptophan is essential for the production and function of rapidly proliferating cells such as lymphocytes. Tryptophan is enzymatically degraded by indoleamine 2,3-dioxygenase (IDO), whose activity is solely dependent on expression of interferon-gamma (IFN-gamma). Because increased expression of IFN-gamma has been reported in trauma patients, we investigated whether enhanced IDO-mediated tryptophan degradation is associated with lymphopenia and poor outcomes after major trauma. The incidence of bacteremic sepsis (BS), adult respiratory distress syndrome (ARDS), multiple organ dysfunction/failure syndromes (MODS/MOF), and death was prospectively documented in 22 trauma patients with a mean ISS of 24.9 +/- 2.2. Sequential blood samples were obtained from admission through postinjury day 10. Five patients developed BS, three of whom developed ARDS; two of the three ARDS patients developed MOF and died on day 10. Trauma patients had significantly lower tryptophan levels (days 1-10), higher kynurenine:tryptophan ratios (days 1-2), and fewer lymphocytes (days 1-4) than healthy volunteers (P < 0.05). Although patients with poor outcomes (i.e., BS, ARDS, MOF, and death) had significantly lower tryptophan levels and greater lymphopenia on several days after injury, the sample size was too small to draw any definitive conclusions. These data indicate that decreased plasma tryptophan levels and lymphopenia typically occur after major trauma. A concomitant increase in kynurenine suggests that the observed tryptophan deficiency is caused, in part, by IDO-mediated tryptophan degradation.

Objectives: Aging is associated with an increased frequency of abnormal immune system function, which may cause infections, autoimmune diseases, and cardiovascular or neurodegenerative disorders. Th1-type cytokine interferon-gamma (IFN-gamma) induces neopterin production as well as tryptophan degradation via indoleamine (2,3)-dioxygenase (IDO), and quantification of these biochemical alterations allows one to monitor immune system activation. Homocysteine is known to be elevated in the elderly, which is possibly due to an insufficient availability of folate, B6, and/or B12., Design and Methods: Serum concentrations of neopterin, homocysteine, tryptophan and kynurenine, and of vitamins folate and B12 were measured in 43 healthy individuals (21 females, 22 males) aged 34-93 years. The ratio of the concentration of the product of IDO, kynurenine, versus the substrate tryptophan (kyn/trp) was calculated to estimate IDO activity., Results: Comparing three age groups of similar size (34-60, 61-71, and 72-93 years), neopterin and homocysteine concentrations as well as the kyn/trp ratio were found to increase with older age (all P < 0.01). Folate concentrations were lower in the middle-aged group as compared with the other two subgroups of individuals. Vitamin B12 concentrations did not differ between groups. Positive correlations were found between kyn/trp and neopterin and homocysteine concentrations (all P < 0.01)., Conclusions: Increasing neopterin concentrations and kyn/trp with older age are in line with the view that aging in healthy people is associated with immune activation especially of the T-cell/macrophage system.

Tibetan herbal remedy PADMA 28 revealed promising results to support treatment of intermittent claudication, atherosclerosis and chronic hepatitis. The remedy was confirmed to be closely linked with anti- and pro-oxidative properties in vitro. In this study, effect of PADMA 28 was investigated in stimulated and unstimulated human peripheral blood mononuclear cells (PBMC) in vitro. Neopterin production and tryptophan degradation were measured in supernatants of PBMC in the presence or absence of mitogens phytohaemagglutinin (PHA) and concanavalin A (Con A). Stimulation of PBMC induced neopterin formation and tryptophan degradation (p<0.001 compared to unstimulated PBMC), and PADMA 28 inhibited both immunobiochemical effects (p<0.001) in a concentration-dependent manner. Higher concentrations of PADMA 28 were more effective and were able to completely block the pathways induced upon mitogenic stimulation. Data allow to conclude that PADMA 28 is able to inhibit immunobiological effects in stimulated PBMC in vitro. The suppression of neopterin production and tryptophan degradation suggests a specific influence on biochemical pathways induced by Th1-type cytokine interferon-gamma., (Copyright 2004 Elsevier B.V.)

N-Chlorotaurine (NCT) plays an important role in the human defense system as a main component of long-lived oxidants, and shows bactericidal, fungicidal, and virucidal activity. Besides this role, NCT seems to act regulatory on immunocompetent cells by altering cytokine production. NCT inhibited nitric oxide, TNF-alpha, and prostaglandin E(2) (PGE(2)) production in activated rodent macrophages, and suppressed superoxide anion, IL-6, and IL-8 formation in human polymorphonuclear leukocytes. In this study, the influence of NCT on the production of neopterin and the activation of the enzyme indoleamine-2,3 dioxygenase (IDO) was investigated in human peripheral blood mononuclear cells (PBMC). Both events are well established to be triggered by IFN-gamma and therefore related to Th1-type immune activation. Mitogen-induced neopterin production as well as tryptophan degradation were drastically reduced upon addition of NCT. Results fit in the concept of a reduction of pro-inflammatory cytokines by this compound. In contrast to earlier results, where NCT was suggested to act primarily down-regulatory on Th2 cells, we propose also a strong suppressive effect of NCT on Th1-type immunity.

Background: Tryptophan (TRP) degradation into kynurenine (KYN) by the enzyme, indoleamine-2,3-dioxygenase, during immune activation may contribute to development of depressive symptoms during interferon (IFN)-alpha therapy., Methods: Twenty-six patients with malignant melanoma were randomly assigned in double-blind fashion to receive either placebo or paroxetine, beginning 2 weeks before IFN-alpha treatment and continuing for the first 12 weeks of IFN-alpha therapy. At treatment initiation and at 2, 4, and 12 weeks of IFN-alpha treatment, measurements of TRP, KYN, and neopterin (a marker of immune activation), were obtained, along with structured assessments of depression, anxiety, and neurotoxicity., Results: Regardless of antidepressant treatment status, all patients exhibited significant increases in KYN, neopterin, and the KYN/TRP ratio during IFN-alpha therapy. Among antidepressant-free patients, patients who developed major depression exhibited significantly greater increases in KYN and neopterin concentrations and more prolonged decreases in TRP concentrations than did nondepressed, antidepressant-free patients. Moreover, in antidepressant-free patients, decreases in TRP correlated with depressive, anxious, and cognitive symptoms, but not neurovegetative or somatic symptoms. No correlations were found between clinical and biological variables in antidepressant-treated patients., Conclusions: The results suggest that reduced TRP availability plays a role in IFN-alpha-induced depressive symptoms, and paroxetine, although not altering the KYN or neopterin response to IFN-alpha, attenuates the behavioral consequences of IFN-alpha-mediated TRP depletion.

Objective: Activation of the enzyme indoleamine-(2,3)-dioxygenase (IDO) by interferon (IFN)-g leads to enhanced tryptophan conversion to kynurenine. In consequence of chronic immune activation, tryptophan availability is reduced, leading to inhibition of cell proliferation as protein synthesis is affected. Tryptophan deprivation due to IDO activation could therefore be effective in abrogating processes with high metabolic turnover, thus modulating cellular immune response., Methods: Concentrations of tryptophan, kynurenine, and neopterin were measured by HPLC in the sera of 38 patients with rheumatoid arthritis (RA). The kynurenine:tryptophan ratios (kyn/trp) were calculated to estimate IDO activity., Results: Tryptophan concentrations were lower in patients with RA (median, interquartile range: 44.95 microM, 40.31-49.95 microM) compared to healthy blood donors (62.62 microM, 57.27-74.61 microM; p < 0.001). Kynurenine in patients (1.86 microM, 1.54-2.31 microM) did not differ from controls (2.06 microM, 1.58-2.65 microM; NS). The kyn/trp ratio was higher in patients (42.39 mM/M, 37.02-48.60 mM/M) than in controls (31.72 mM/M; 27.95-35.03 mM/M; p < 0.001). Kynurenine concentrations (rs = 0.611; p < 0.001) and kyn/trp ratios (rs = 0.621; p < 0.001) correlated with neopterin concentrations, which indicate stimulated cellular immune response in patients with RA., Conclusions: The data point to a role of immune activation and Th1-type cytokine INF-g to induce elevated tryptophan degradation in patients with RA.

Tryptophan is an essential amino acid and the least abundant constituent of proteins. In parallel it represents a source for two important biochemical pathways: the generation of neurotransmitter 5-hydroxytryptamine (serotonin) by the tetrahydrobiopterin-dependent tryptophan 5-hydroxylase, and the formation of kynurenine derivatives and nicotinamide adenine dinucleotides initiated by the enzymes tryptophan pyrrolase (tryptophan 2,3-dioxygenase, TDO) and indoleamine 2,3-dioxygenase (IDO). Whereas TDO is located in the liver cells, IDO is expressed in a large variety of cells and is inducible by the cytokine interferon-gamma. Therefore, accelerated tryptophan degradation is observed in diseases and disorders concomitant with cellular immune activation, e. g. infectious, autoimmune, and malignant diseases, as well as during pregnancy. According to the cytostatic and antiproliferative properties of tryptophan-depletion on T lymphocytes, activated T-helper type 1 (Th-1) cells may down-regulate immune response via degradation of tryptophan. Especially in states of persistent immune activation availability of free serum tryptophan is diminished and as a consequence of reduced serotonin production, serotonergic functions may as well be affected. Accumulation of neuroactive kynurenine metabolites such as quinolinic acid may contribute to the development of neurologic/psychiatric disorders. Thus, IDO seems to represent a link between the immunological network and neuroendocrine functions with far reaching consequences in regard to the psychological status of patients. These observations provide a basis for the better understanding of mood disorder and related symptoms in chronic diseases.

Hypercholesterolemia is associated with an increased risk of atherosclerosis and coronary heart disease. Therefore, therapeutic lowering of cholesterol is an important preventive measure of cardiac morbidity and death. As one side effect, cholesterol-lowering drugs appear to increase the mortality due to suicides or violence, and low lipid concentrations were found to be associated with trait measures of depression. We compared serum cholesterol concentrations and the Beck Depression Rating Scale (Beck's score) in 604 otherwise healthy outpatients who visited the physician's office for a medical health check-up; 65.4% of individuals presented with serum cholesterol concentrations > or = 5.2 mmol/l (> 200 mg/dl) and 5.3% had elevated Beck's score (> 19), indicative for depression. Beck's score was higher in patients with cholesterol concentrations above the 75th percentile (= 6.2 mmol/l; U = 31221, p < 0.02, Mann-Whitney U-test), and Beck's score correlated with cholesterol concentrations and with age. Thus, in contrast to the widely accepted view, in our study, higher cholesterol concentrations were associated with signs of depressive mood. Hypercholesterolemia may not necessarily increase the risk of depressive mood, conversely, increased intake of fat and carbohydrates by individuals with depressive mood may increase cholesterol levels.

Neopterin (Neo) and 7,8-dihydroneopterin (H(2)Neo) are produced by human monocyte-derived macrophages upon stimulation with IFN-gamma. Increased amounts of Neo and H(2)Neo in human body fluids are found in many disorders, including viral infections and autoimmune diseases. Recent data suggest that neopterin derivatives may exhibit distinct biochemical functions activating redox-sensitive transcription factors and inducing apoptosis in various cell lines. In this study we investigated the effect of H(2)Neo on human peripheral blood T cells (PBT) from healthy blood donors in comparison with PBT isolated from patients with systemic lupus erythematosus (SLE). H(2)Neo induced apoptosis in healthy PBT in a concentration-dependent manner. In short time culture, a significantly lower ability of PBT isolated from patients with SLE to undergo apoptosis in response to H(2)Neo compared to healthy controls was detected. Our results suggest a possible role of the neopterin derivative H(2)Neo in T cell apoptosis mediated by stimulated monocytes/macrophages.