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Indoleamine 2,3-dioxygenase 1 (IDO1) is a cytosolic haem-containing enzyme involved in the degradation of tryptophan to kynurenine. Although initially thought to be solely implicated in the modulation of innate immune responses during infection, subsequent discoveries demonstrated IDO1 as a mechanism of acquired immune tolerance. In cancer, IDO1 expression/activity has been observed in tumor cells as well as in the tumor-surrounding stroma, which is composed of endothelial cells, immune cells, fibroblasts, and mesenchymal cells. IDO1 expression/activity has also been reported in the peripheral blood. This manuscript reviews available data on IDO1 expression, mechanisms of its induction, and its function in cancer for each of these compartments. In-depth study of the biological function of IDO1 according to the expressing (tumor) cell can help to understand if and when IDO1 inhibition can play a role in cancer therapy.

Indoleamine 2,3-dioxygenase 1 (IDO1) is a cytosolic haem-containing enzyme involved in the degradation of tryptophan to kynurenine. Although initially thought to be solely implicated in the modulation of innate immune responses during infection, subsequent discoveries demonstrated IDO1 as a mechanism of acquired immune tolerance. In cancer, IDO1 expression/activity has been observed in tumor cells as well as in the tumor-surrounding stroma, which is composed of endothelial cells, immune cells, fibroblasts, and mesenchymal cells. IDO1 expression/activity has also been reported in the peripheral blood. This manuscript reviews available data on IDO1 expression, mechanisms of its induction, and its function in cancer for each of these compartments. In-depth study of the biological function of IDO1 according to the expressing (tumor) cell can help to understand if and when IDO1 inhibition can play a role in cancer therapy. [ABSTRACT FROM AUTHOR]

The human immunodeficiency virus (HIV) accesses the central nervous system (CNS) early during infection, leading to HIV-associated cognitive impairment and establishment of a viral reservoir. Here, we describe a dichotomy in inflammatory responses in different CNS regions in simian immunodeficiency virus (SIV)-infected macaques, a model for HIV infection. We found increased expression of inflammatory genes and perivascular leukocyte infiltration in the midbrain of SIV-infected macaques. Conversely, the frontal lobe showed downregulation of inflammatory genes associated with interferon-γ and interleukin-6 pathways, and absence of perivascular cuffing. These immunologic alterations were not accompanied by differences in SIV transcriptional activity within the tissue. Altered expression of genes associated with neurotoxicity was observed in both midbrain and frontal lobe. The segregation of inflammatory responses to specific regions of the CNS may both account for HIV-associated neurological symptoms and constitute a critical hurdle for HIV eradication by shielding the CNS viral reservoir from antiviral immunity.

The article discusses a study related to immune responses in the central nervous system (CNS) regions in simian immunodeficiency virus (SIV)-infected macaques for human immunodeficiency virus (HIV) infection. It mentions role of the antiretroviral therapy to effectively control HIV replication in the majority of patients.

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

Nigella sativa, commonly known as black cumin seed, belongs to the botanical family of Ranunculaceae. The active antioxidant components of Nigella sativa display a remarkable array of biochemical, immunological and pharmacological actions, including bronchodilatory, anti-inflammatory, antibacterial, hypoglycaemic, antitumoural and immunopotentiating effects. Effects of Nigella sativa seeds extracts were investigated in freshly isolated human peripheral blood mononuclear cells stimulated with the mitogens phytohaemagglutinin and concanavalin A in vitro. Tryptophan degradation and neopterin production were monitored in culture supernatants, both these immunobiochemical pathways are induced by pro-inflammatory cytokine interferon-γ. Compared to unstimulated cells, the mitogens enhanced degradation of tryptophan and production of neopterin. Nigella sativa seeds extracts significantly suppressed both pathways in a dose-dependent way. Suppression of tryptophan degradation and neopterin formation by Nigella sativa seeds extracts demonstrates an inhibitory influence on activated T-cells and macrophages. Data are in line with an anti-inflammatory activity of the extracts.

Thl-type cytokine interferon-y induces neopterin production in human monocyte-derived macrophages and it stimulates enzyme indoleamine (2,3)-dioxygenase (IDO) which converts tryptophan to kynurenine in various cells. In an integrative single-case study, a healthy, 27-year-old female had collected her entire urine in 12-hour (= I lag) intervals on 56 consecutive days. Neopterin, tryptophan, kynurenine and Creatinine concentrations were determined using HPLC. The kynurenine to tryptophan ratio (kyn/trp) was calcuiated as an index for IDO activity. Within the Observation period, the woman experienced an infection episode presenting with vomiting and headache, however, not serologically verified. During this period, strong increases in both urinary kyn/trp and neopterin to Creatinine concentrations were observed, and thcrc was a significant correlation between neopterin/creatinine and kyn/trp at the same day (rs =0.334, 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.

ENGIN A.B., OZKAN Y., FUCHS D. & YARDIM-AKAYDIN S. (2009) European Journal of Cancer Care Increased tryptophan degradation in patients with bronchus carcinoma Expression of tryptophan-degrading enzyme indoleamine (2,3)-dioxygenase in tumour tissue is proposed to represent an important tumour immunoescape mechanism. To further investigate the potential role of activated indoleamine (2,3)-dioxygenase in bronchus carcinoma, we examined serum tryptophan and kynurenine concentrations in nine patients with small cell lung cancer and in 27 patients with non-small cell lung cancer. Tryptophan metabolic changes were compared with markers of inflammation and immune activation namely C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and neopterin. Compared with controls, patients presented with lower tryptophan concentrations ( P < 0.01) and with higher serum kynurenine to tryptophan ratios ( P < 0.01), an index of tryptophan degradation. Also ESR and CRP and neopterin concentrations were increased in the patients (all P < 0.001), and there was a weak correlation between kynurenine to tryptophan ratio and ESR, CRP and neopterin concentrations. We conclude that in the majority of patients with non-small cell lung cancer and small cell lung cancer, enhanced tryptophan degradation can be observed. It seems to relate to an inflammatory response and may reflect activation of indoleamine (2,3)-dioxygenase at the tumour site. The capacity of the tumour to escape normal host immune defence may be influenced by tryptophan degradation. Results of this pilot study deserve further confirmation. [ABSTRACT FROM AUTHOR]

Abstract: Intrathecal production of neopterin, a pteridine produced by interferon (IFN)-γ-stimulated monocyte-derived macrophages, is associated with neurological disorders and infections. We investigated whether IFN-α/β, IFN-γ, or human immunodeficiency virus (HIV) induce neopterin production by human astroglioma cells. IFN-α/β and IFN-γ, but not HIV, induced neopterin. Interestingly, IFN-γ, but not IFN-α/β, increased expression and activity of the tryptophan-catabolizing enzyme indoleamine (2,3)-dioxygenase. In contrast, IFN-α/β, but not IFN-γ, 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. [Copyright &y& Elsevier]

Abstract: Antitumor activity of a calcium-pterin suspension has been described in vitro and in animal model systems. Recent studies provide some evidence that this effect involves immune-mediated mechanisms. We investigated the influence of calcium-pterin on freshly isolated human peripheral blood mononuclear cells (PBMC) stimulated with the mitogens phytohaemagglutinin and concanavalin A in vitro. Influence of calcium-pterin on tryptophan-degrading enzyme indoleamine (2,3)-dioxygenase (IDO) and on neopterin production was monitored in supernatants of cells. Increased neopterin concentrations as well as accelerated tryptophan degradation have been found to predict poor prognosis in patients with cancer, and both these immunobiochemical pathways are induced by the pro-inflammatory cytokine interferon-γ. Compared to unstimulated cells, mitogens induced degradation of tryptophan and formation of neopterin in PBMC, and upon addition of calcium-pterin, both biochemical results were suppressed in a dose-dependent way. Thus, calcium-pterin suppresses immunological pathways in vitro that in patients with malignant diseases characterize an unfavorable prognosis. The effect of the compound to suppress IDO activity could be of considerable relevance for the antitumoral effect of the compound because activation of the enzyme is considered as an immune-escape mechanism of tumor cells. [Copyright &y& Elsevier]

Abstract: Antioxidant preservatives prolong the quality of food and ensure the nutritional adequacy, palatability and safety of many processed foods and beverages. Effects of sodium sulfite (E221) and sorbic acid (E200) were investigated in human peripheral blood mononuclear cells (PBMC) which were purified from blood of healthy donors. Cells were stimulated with the mitogen phytohaemagglutinin in vitro, which induces proliferation of T-cells and the production of Th1-type cytokines like interferon-γ. The latter triggers enzyme indoleamine (2,3)-dioxygenase, which degrades tryptophan, and GTP cyclohydrolase I, which leads to increased neopterin production, in monocyte-derived macrophages. Sodium sulfite and sorbic acid suppressed both these biochemical changes in a dose-dependent way (P <0.01 at 1mM sodium sulfite and 50mM sorbic acid). Data demonstrate a suppressive influence of sodium sulfite and sorbic acid on the activated Th1-type immune response. [Copyright &y& Elsevier]

Immune system activation is known to be involved in the progression of rheumatoid arthritis (RA). The proinflammatory cytokine interferon-γ in various cells, including monocytes, induces the enzyme indoleamine (2,3)-dioxygenase (IDO), which converts tryptophan to kynurenine. In sera of 22 patients (17 women and 5 men) with RA stages 1 to 4 according to Steinbrocker, the concentrations of tryptophan and kynurenine were measured by high-pressure liquid chromatography. To estimate IDO activity, the kynurenine to tryptophan ratio (kyn/trp) was calculated. In parallel, concentrations of the macrophage activation marker neopterin were determined by enzyme-linked immunosorbent assay. Tryptophan concentrations were lower in patients with RA, and the decrease in serum tryptophan correlated with increase in stage ( p<0.05). Kyn/trp correlated well with neopterin concentrations, which were elevated in most patients. Whereas higher C-reactive protein concentrations and erythrocyte sedimentation rates were observed in patients with greater disease activity, tryptophan and neopterin concentrations did not differ between patients with different subjective disease activity graded by the physician. Deficiency of the essential amino acid tryptophan in patients with RA most likely results from immune activation involved in the pathogenesis of the disease. It could also be relevant for the mood of patients, as tryptophan is the precursor of serotonin. [ABSTRACT FROM AUTHOR]

Abstract: Moderate consumption of alcoholic beverages is suggested to reduce cardiovascular risk. Within this context, most attention is drawn to antioxidant ingredients of wine, but also beer was found to be beneficial. Potential effects of three different types of beer including alcohol-free beer were investigated using freshly isolated human peripheral blood mononuclear cells stimulated with the mitogen phytohaemagglutinin in vitro. Neopterin production and tryptophan degradation were monitored in culture supernatants to determine effects of test substances on immunobiochemical pathways induced by interferon-γ. In a subgroup of experiments also production of interferon-γ was measured. Compared to unstimulated cells, phytohaemagglutinin increased production of neopterin and also triggered the degradation of tryptophan (all p <0.01). All types of beer (2–4% dilution) were found to counteract these stimulation-induced effects and significant reduction of neopterin formation and tryptophan degradation was observed (p <0.01). Data demonstrate that beer reduces production of neopterin and degradation of tryptophan, both these biochemical pathways are induced during cell-mediated immune response. Data suggest that the immunosuppressive capacity of beer may relate to its anti-inflammatory nature. [Copyright &y& Elsevier]

Abstract: The essential amino acid tryptophan is a constituent of proteins and is also a substrate for two important biosynthetic pathways: the generation of neurotransmitter 5-hydroxytryptamine (serotonin) by tryptophan 5-hydroxylase, and the formation of kynurenine derivatives and nicotinamide adenine dinucleotides. The latter pathway is initiated by the enzymes tryptophan pyrrolase (tryptophan 2,3-dioxygenase, TDO) and indoleamine 2,3-dioxygenase (IDO). TDO is located in liver cells, whereas IDO is expressed in a variety of cells including monocyte-derived macrophages and dendritic cells and is preferentially induced by Th1-type cytokine interferon-γ. Tryptophan depletion via IDO is part of the cytostatic and antiproliferative activity mediated by interferon-γ in cells. In vivo tryptophan concentration can be measured by HPLC by monitoring its natural fluorescence (285 nm excitation and 365 nm emission wavelength). IDO activity is characterized best by the kynurenine to tryptophan ratio which correlates with concentrations of immune activation markers such as neopterin. Low serum/plasma tryptophan concentration is observed in infectious, autoimmune, and malignant diseases and disorders that involve cellular (Th1-type) immune activation as well as during pregnancy due to accelerated tryptophan conversion. Thus, in states of persistent immune activation, low tryptophan concentration may contribute to immunodeficiency. Decreased serum tryptophan can also effect serotonin biosynthesis and thus contribute to impaired quality of life and depressive mood. As such, monitoring tryptophan metabolism in chronic immunopathology provides a better understanding of the association between immune activation and IDO and its role in the development of immunodeficiency, anemia and mood disorders. [Copyright &y& Elsevier]

St. John's wort ( Hypericum perforatum) is an ancient folk remedy that has antiviral and antibacterial properties. Anti-inflammatory effects of the plant have been described and the application of H. perforatum extract as an effective antidepressant is well established. In this study we assayed the effect of H. perforatum extract on cytokine-induced tryptophan degradation in human peripheral blood mononuclear cells. Simultaneously, changes in the production of the immune activation marker neopterin were monitored. Both these biochemical pathways are triggered by interferon-?. Our results show that extracts of H. perforatum strongly down-regulate mitogen-mediated tryptophan degradation in a dose-dependent manner. This effect seems to be based on a suppressive activity of H. perforatum on activated immunocompetent cells, resulting in a diminished production of interferon-?. In line with this finding, neopterin synthesis was strongly down-regulated by the plant extract. Our results suggest that the reduction of tryptophan degradation by H. perforatum might be important in the action of the plant as an antidepressant. [ABSTRACT FROM AUTHOR]

The cytokine interferon-γ stimulates human monocytes/macrophages to release large amounts of neopterin. Increased neopterin concentrations in body fluids of patients are observed during diseases with activated cellular (=TH1-type) immune response such as allograft rejection, virus infections, autoimmune disorders, or malignant tumors but also in neurodegenerative diseases or during pregnancy. In various cells interferon-γ induces indoleamine 2,3-dioxygenase (IDO) which degrades tryptophan via the kynurenine pathway. Therefore like increased neopterin formation, enhanced tryptophan degradation is observed in diseases concomitant with cellular immune activation. Disturbed metabolism of tryptophan affects biosynthesis of neurotransmitter 5-hydroxytryptamine (serotonin), and it appears to be associated with an increased susceptibility for depression. In fact, enhanced neopterin concentrations together with increased degradation of tryptophan and low serum levels of tryptophan correlate with neuropsychiatric abnormalities like cognitive decline and depressive symptoms especially in long-lasting and chronic diseases. Activation of IDO could represent an important link between the immunological network and the pathogenesis of depression. [Copyright &y& Elsevier]

The potential effects of globularifolin, an acylated iridoid glucoside, on cell survival, inflammation markers and free radicals scavenging were investigated. Viability assay on human myelomomonocytic cell line THP-1 and human peripheral blood mononuclear cells (PBMC) using the Cell-Titer Blue assay proved that globularifolin had no toxic effect at the tested concentrations. Conversely, it is proportional to the dose globularifolin increased growth of THP-1 cells (p <0.01). On human PBMC, globularifolin at 6.25 and 12.5 μM concentrations showed a stimulatory effect, while at 12.5-200 μM it suppressed response of PBMC to stimulation with phytohemagglutinin (PHA). Globularifolin (50-200 μM) enhanced neopterin formation dose-dependently, whereas tryptophan breakdown was not influenced. At 50-200 μM in unstimulated PBMC in THP-1 cells, globularifolin induced a significant expression of nuclear factor-κB (NF-κB) as was quantified by Quanti-Blue assay. By contrast, in lipopolysaccharide (LPS)-stimulated cells, the higher concentrations of globularifolin suppressed NF-κB expression dose-dependently and a significant decrease was observed at 200 μM concentration. A positive correlation was found between increased neopterin and NF-κB activity (p <0.01). Similarly, a positive correlation was observed between neopterin levels in mitogen-induced cells and NF-κB activity in LPS-stimulated cells after treatment with globularifolin (p=0.001). The free radical scavenging capacity of globularifolin evaluated by Oxygen Radical Absorbance Capacity (ORAC) assay showed relative ORAC values of 0.36±0.05 μmol Trolox equivalent/μmol. All together, results show that natural antioxidant globularifolin might represent a potential immunomodulatory as well as proliferative agent, which deserves further in vitro and in vivo studies., (© 2013.)