Ifn-γ Activated Indoleamine 2,3-Dioxygenase Activity in Human Cells is an Antiparasitic and an Antibacterial Effector Mechanism

Institute for Medical Microbiology and Virology, Heinrich-Heine Universität Düsseldorf.
Advances in Experimental Medicine and Biology (Impact Factor: 1.96). 02/1999; 467:517-24. DOI: 10.1007/978-1-4615-4709-9_64
Source: PubMed


In nearly all human cells IFN-gamma stimulation leads to an activation of indoleamine 2,3-dioxygenase (IDO) activity, which is responsible for anti-toxoplasma and anti-chlamydia effects. We have recently shown that IDO activation is also a defense mechanism against extracellular beta-hemolytic streptococci groups A, B, C and G in human glioblastoma cells, fibroblasts and macrophages. Similar effects were also seen with enterococci and in approximately 65% of staphylococci tested, including multiresistant strains of both species. In addition, we have found that IDO activity is differentially regulated in different cells. For example we have found that TNF-alpha enhances IFN-gamma induced IDO activity and antimicrobial effect in human glioblastoma cells whereas both IFN-gamma mediated effects were blocked by TNF-alpha as well as by IL-1 in a human uroepithelial cell line. We were able to show that the IL-1 and TNF-alpha mediated inhibition of IFN-gamma-induced IDO activity in uroepithelial cells is due to stimulation of inducible nitric oxide synthase. In human astrocytoma cells, IL-1 and TNF-alpha did not inhibit IDO activity and in concordance with this finding these cells did not show a detectable nitric oxide production.

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    • "IDO is induced mainly by interferon-γ [5,6] and to a lesser extent by interferon-α [7] and its activity can be modulated by both pro- and anti-inflammatory cytokines and mediators in various ways (for references, see [8]). The resultant decrease in [Trp] after IDO induction by interferon-γ is thought to underlie the antiparasitic, antibacterial and antiproliferative actions of this major cytokine [9,10]. "
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    ABSTRACT: The decrease in maternal plasma total (free + albumin-bound) tryptophan (Trp) during the third pregnancy trimester is attributed to induction of indoleamine 2,3-dioxygenase (IDO). When measured, free [Trp] is increased because of albumin depletion and non-esterified fatty acid elevation. The Trp depletion concept in pregnancy is therefore not supported because of incorrect interpretation of changes in Trp disposition and also for not addressing mouse strain differences in Trp-related responses and potential inhibition of Trp transport by the IDO inhibitor 1-methyl tryptophan. Application of the Trp utilization concept in pregnancy offers several physiological advantages favoring fetal development and successful outcome, namely provision of Trp for fetal protein synthesis and growth, serotonin for signaling pathways, kynurenic acid for neuroprotection, quinolinic acid for NAD(+) synthesis, and other kynurenines for suppression of T cell responses. An excessive increase in Trp availability could compromise pregnancy by undermining T cell suppression, e.g., in pre-eclampsia.
    07/2014; 57(4):249-259. DOI:10.5468/ogs.2014.57.4.249
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    • "In immunocompetent hosts, infection with T. gondii leads to the production of interferon-γ (IFN-γ) and, consequently, the induction of indoleamine 2,3-dioxygenase (IDO), which converts the essential amino acid tryptophan to kynurenine and inhibits T. gondii growth in vitro (Dai et al., 1994; Däubener and MacKenzie, 1999) and in vivo (Silva et al., 2002). Kynurenine, in turn, is further degraded via a "
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    ABSTRACT: Toxoplasma gondii, an intracellular protozoan parasite, is a major cause of opportunistic infectious disease affecting the brain and has been linked to an increased incidence of schizophrenia. In murine hosts, infection with T. gondii stimulates tryptophan degradation along the kynurenine pathway (KP), which contains several neuroactive metabolites, including 3-hydroxykynurenine (3-HK), quinolinic acid (QUIN) and kynurenic acid (KYNA). As these endogenous compounds may provide a mechanistic connection between T. gondii and the pathophysiology of schizophrenia, we measured KP metabolites in both the brain and periphery of T. gondii-treated C57BL/6 mice 8 and 28days post-infection. Infected mice showed early decreases in the levels of tryptophan in the brain and serum, but not in the liver. These reductions were associated with elevated levels of kynurenine, KYNA, 3-HK and QUIN in the brain. In quantitative terms, the most significant increases in these KP metabolites were observed in the brain at 28days post-infection. Notably, the anti-parasitic drugs pyrimethamine and sulfadiazine, a standard treatment of toxoplasmosis, significantly reduced 3-HK and KYNA levels in the brain of infected mice when applied between 28 and 56days post-infection. In summary, T. gondii infection, probably by activating microglia and astrocytes, enhances the production of KP metabolites in the brain. However, during the first two months after infection, the KP changes in these mice do not reliably duplicate abnormalities seen in the brain of individuals with schizophrenia.
    Schizophrenia Research 12/2013; 152(1). DOI:10.1016/j.schres.2013.11.011 · 3.92 Impact Factor
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    • "In the past years, IDO has emerged as an important regulator of the immune system; however, it is not known whether local IDO activity is beneficial or detrimental to inflamed tissues. IDO is induced by interferon γ (IFN-γ) and other inflammatory cytokines during inflammation or as a consequence of normal tissue function [4]. IDO suppresses T cell activity and promotes T cell tolerance to further antigenic challenges, by promoting the differentiation of naïve CD4 T cells into regulatory T cells, putatively by regulation by dendritic cells [5-10]. "
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    ABSTRACT: Indoleamine 2,3-dioxygenase (IDO) is a tryptophan catalyzing enzyme. It has been suggested that it has a role in lower airway allergic inflammations, but its role in allergic rhinitis has not been investigated. Our aim was to evaluate the expression of IDO in the nasal mucosa of allergic rhinitis patients allergic to birch pollen during peak exposure to birch pollen allergen and compare it to non-atopic patients. IDO expression was immunohistochemically evaluated from nasal specimens obtained in- and off-season from otherwise healthy non-smoking volunteers both allergic to birch pollen (having mild or moderate allergic rhinoconjunctivitis) and non-allergic controls. Results: The IDO expression levels were low in healthy controls and remained low also in patients allergic to birch pollen. There were no differences in the expression of IDO in- and off-season in either healthy or allergic subjects. There is a controversy in the role of IDO in upper and lower airways during allergic airway disease. It seems that IDO is associated to allergic inflammations of the lower airways, but does not have a local role in the nasal cavity at least in mild or moderate forms of allergic rhinitis.
    12/2011; 1(1):17. DOI:10.1186/2045-7022-1-17
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