Article

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

ABSTRACT

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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    • "However, another endogenous metabolite, picolinic acid (PIC) can antagonise the excitotoxic effects of QUIN without affecting its neurotoxic effects through an undetermined mechanism [Jhamandas et al., 1990, 2000] Activated by interferon gamma [Daubener and MacKenzie, 1999] indoleamine-2,3-dioxygenase (IDO1) is one of the first enzymes triggering the activation of the KP and is responsible for the oxidative metabolism of TRYP [Thomas and Stocker, 1999; Fujigaki et al., 2006]. It has already been shown that human fetal skin fibroblasts and keratinocytes express IDO1 and produce kynurenine. "
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    ABSTRACT: Acute UVB exposure triggers inflammation leading to the induction of indoleamine 2,3 dioxygenase (IDO1), one of the first enzymes in the kynurenine pathway (KP) for tryptophan degradation. However, limited studies have been undertaken to determine the catabolism of tryptophan within the skin. The aim of this study was two-fold: (1) to establish if the administration of the proinflammatory cytokine interferon-gamma (IFN-γ) and/or UVB radiation elicits differential KP expression patterns in human fibroblast and keratinocytes, and (2) to evaluate the effect of KP metabolites on intracellular nicotinamide adenine dinucleotide (NAD+) levels, and cell viability. Primary cultures of human fibroblasts and keratinocytes were used to examine expression of the KP at the mRNA level using qPCR, and at the protein level using immunocytochemistry. Cellular responses to KP metabolites were assessed by examining extracellular lactate dehydrogenase (LDH) activity and intracellular NAD+ levels. Major downstream KP metabolites were analysed using GC/MS and HPLC. Our data shows that the KP is fully expressed both in human fibroblasts and keratinocytes. Exposure to UVB radiation and/or IFN-γ causes significant changes in the expression pattern of downstream KP metabolites and enzymes. Exposure to various concentrations of KP metabolites showed marked differences in cell viability and intracellular NAD+ production, providing support for involvement of the KP in the de novo synthesis of NAD+ in the skin. This new information will have a significant impact on our understanding of the pathogenesis of UV related skin damage and the diagnosis of KP related disease states. This article is protected by copyright. All rights reserved
    Full-text · Article · Jan 2015 · Journal of Cellular Biochemistry
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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.
    Full-text · Article · Jul 2014
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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.
    Full-text · Article · Dec 2013 · Schizophrenia Research
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