Restriction of<i>Toxoplasma gondii</i>Growth in Human Brain Microvascular Endothelial Cells by Activation of Indoleamine 2,3-Dioxygenase

Däubener, Walter; Spors, Birgit; Hucke, Christian; Adam, Rüdiger; Stins, Monique F.; Kim, Kwang Sik; Schroten, Horst

doi:10.1128/iai.69.10.6527-6531.2001

Cited by 115 publications

(75 citation statements)

References 25 publications

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“…Additionally, we have recently shown that human astrocytoma cells exhibit strong IDO activation after stimulation with IFN-␥ (12). There is an increasing body of evidence indicating that IDO activation in human cells is a potent antiparasitic and antibacterial effector mechanism (7,9,10,11,27,33,39). That viruses are also controlled by IDO activation in human cells was first indicated by Bogdahi et al in 1999 (3).…”

Section: Gamma Interferon (Ifn-mentioning

confidence: 99%

Role of Indoleamine-2,3-Dioxygenase in Alpha/Beta and Gamma Interferon-Mediated Antiviral Effects against Herpes Simplex Virus Infections

Adams

Besken

Oberdörfer

et al. 2004

J Virol

106

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Gamma interferon (IFN-␥Human herpes simplex virus (HSV) type 1 (HSV-1) and HSV-2, along with varicella-zoster virus, are classified in the alpha-herpesvirus subfamily of herpesviruses whose presence leads to an establishment of latency in neural ganglia (43). The most serious infection caused by HSV-1 is sporadic encephalitis, with an untreated mortality rate of approximately 70% (24, 42). Generally, in immunocompromised patients HSV-1 infections are often severe. A locally invasive infection may result in mucocutaneous necrosis and spread to contiguous organs, resulting in (for example) esophagitis or leading to viremia, with subsequent distant organ manifestations such as meningoencephalitis, pneumonitis, and hepatitis (25,26,31,35,44).Studies conducted using animal models of HSV-1 infections and animal and human cells have shown that control of the primary infection and reactivation depends on the host immune system (1,14,34), where the production of interferons (IFNs) plays a key role (23).Two distinct but functionally overlapping types of IFNs are known: alpha/beta IFNs (IFN-␣/␤), which include some species of IFN-␣ and a single IFN-␤, and IFN-␥ (36). Within the last decades several IFN-induced effector mechanisms for the control of viruses have been described. These include the expression of double-stranded RNA-dependent protein kinase (22), Mx proteins (19), 2Ј-5Ј oligoadenylate synthase, and RNase L (15). The most prominent IFN-inducible antimicrobial effector mechanism for the control of parasitic, bacterial, and viral growth in murine cells is NO production by the inducible isoform of nitric oxide synthase (iNOS) (4). However, there are only few studies showing an antimicrobial effect mediated by the induction of NO in human cells. In contrast there are abundant published data showing antibacterial and antiparasitic effects mediated by the induction of indoleamine-2,3-dioxygenase (IDO) in human cells (3,7,27,33).MacKenzie et al. and Pfefferkorn have indicated that after stimulation with IFN-␥, human astrocytes and astrocytoma cells are capable of inhibiting the growth of the parasite Toxoplasma gondii and of group B streptococci (27, 33). In both cases, the activation of IDO and the subsequent degradation of the essential amino acid L-tryptophan were found to comprise the effector mechanism involved. In 1999 Bodaghi et al. (3) showed that IDO activation is also responsible for the inhibition of the growth of human cytomegalovirus in retinal pigment epithelial cells. In this report we show that IFN-␥-induced IDO activity is a potent antiviral effector mechanism for the control of HSV in astrocytes, which are considered to play a key role in HSV-encephalitis. In contrast, IDO-mediated tryptophan depletion is not involved in the antiviral effects mediated by IFN-␣/␤. IFNs mediate antiviral effects in astrocytoma cells. To determine whether IFN-␣/␤ and IFN-␥ induce an antiviral state in different astrocytoma cells, we stimulated 86HG39 cells (2) (kindly provided by T. Bilzer, Institute of Neuropathology, D...

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Section: Gamma Interferon (Ifn-mentioning

confidence: 99%

Role of Indoleamine-2,3-Dioxygenase in Alpha/Beta and Gamma Interferon-Mediated Antiviral Effects against Herpes Simplex Virus Infections

Adams

Besken

Oberdörfer

et al. 2004

J Virol

106

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“…Standard Western blot analysis for IDO protein expression was performed. 18 IDO enzyme activity following IFN-␥ stimulation of MSCs was measured by tryptophan-to-kynurenine conversion with photometric determination of kynurenine concentration in the supernatant as the readout. 19 In addition, IDO activity was quantified in MSC/MLR cocultures.…”

Section: Detection Of Ido Expression and Activitymentioning

confidence: 99%

Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase–mediated tryptophan degradation

Meisel

Zibert

Laryea

et al. 2004

Blood

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1,528

1,228

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IntroductionHuman bone marrow stromal cells (MSCs), more recently referred to as mesenchymal stem cells, are capable of differentiating along multiple mesenchymal lineages in addition to supporting hematopoiesis. 1,2 Due to their potential for differentiation into osteocytes, chondrocytes, myocytes, and adipocytes, MSCs have emerged as a promising tool for clinical applications such as tissue engineering and cell and gene therapy. 3,4 MSCs are of inherently low immunogenicity and, more importantly, are capable of inhibiting allogeneic T-cell responses. 5-8 These intriguing observations have prompted clinical studies to investigate cotransplantation of MSCs in allogeneic hematopoietic stem cell transplantation (HSCT) in order to promote hematopoietic engraftment by preventing host-versusgraft reactivity and to suppress graft-versus-host reactions. 9,10 As of yet, the molecular mechanisms responsible for the immunosuppressive effects of MSCs have not been unequivocally identified. The reports describing a potential role of transforming growth factor-␤1 and hepatocyte growth factor as mediators of T-cell inhibition remain controversial, but most studies agree that soluble factors are involved. [6][7][8]11 In professional antigen-presenting cells (APCs), expression of indoleamine 2,3-dioxygenase (IDO) induced by interferon-␥ (IFN-␥) and other proinflammatory cytokines catalyzes conversion from tryptophan to kynurenine and has recently been identified as a major immunosuppressive effector pathway that inhibits T-cell responses to autoantigens and fetal alloantigens in vivo. [12][13][14][15][16] Based on these findings, we investigated whether MSCs exhibit IFN-␥-inducible IDO activity and whether this mechanism contributes to T-cell inhibition mediated by MSCs. Study design Culture of human bone marrow-derived MSCsBone marrow aspirates were harvested from volunteer donors who had provided informed consent; the study was approved by the institutional review board of the University Clinic, Düsseldorf, Germany. Primary human MSCs were generated as previously described 17 except that culture medium was supplemented with 3 ng/mL basic fibroblast growth factor (R&D Systems, Minneapolis, MN). Mixed lymphocyte reactions (MLRs)Standard 5-day MLR cultures were set up with 5 ϫ 10 4 mitomycin C-treated human peripheral blood mononuclear cells (PBMCs) as stimulators and 2 ϫ 10 5 human T cells purified using sheep red blood cell rosetting as responder cells. 5,11 In MSC/MLR coculture experiments, MLRs were performed on a layer of either 5 ϫ 10 3 or 2 ϫ 10 4 MSCs seeded one day before. IFN-␥ concentration was determined in MSC/MLR coculture supernatants using a commercially available enzyme-linked immunosorbent assay (ELISA; R&D Systems) according to manufacturer's instructions. Detection of IDO expression and activityMSCs were stimulated with IFN-␥ (R&D Systems) and assayed for IDO expression and function. Standard Western blot analysis for IDO protein expression was performed. 18 IDO enzyme activity following IFN-␥ stimulation of ...

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“…TNF␣ increases in vitro the number of cysts formed in human fibroblasts, involving the activity of an acidic sphingomyelinase (8). TNF␣ acts synergistically with IFN␥ against cerebral toxoplasmosis by inducing indoleamine 2,3-dioxygenase activity, which degrades tryptophan, resulting in an antiparasitic mechanism in brain cells (9,10). Acute toxoplasmosis that causes rapid death in mice is accompanied by high levels of type 1 cytokines in the serum, including IFN␥ and TNF␣ (11).…”

mentioning

confidence: 99%

Roles of Glycosylphosphatidylinositols of Toxoplasma gondii

Debierre‐Grockiego¹,

Azzouz²,

Schmidt³

et al. 2003

Journal of Biological Chemistry

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Toxoplasma gondii is a ubiquitous parasitic protozoan, which causes congenital infectious diseases as well as severe encephalitis, a major cause of death among immune-deficient persons, such as AIDS patients. T. gondii is normally controlled by the immune system of healthy individuals, leading to an asymptomatic infection. T. gondii triggers early cytokine production, which, to a certain extent, protects the host against replication of tachyzoites, the infective form of the parasite. Glycosylphosphatidylinositols (GPIs) constitute a class of glycolipids that have various functions, the most fundamental being to link proteins to eucaryotic cell membranes. GPIs are involved in the pathogenicity of other protozoan parasites and are known to induce tumor necrosis factor-␣ (TNF␣) production. We show that GPIs highly purified from T. gondii tachyzoites, as well as their core glycans, induce TNF␣ production in macrophages. A chemically synthesized GPI of T. gondii lacking its lipid moiety, GPIa, has the same effect as the natural GPIs, whereas a chemically synthesized molecule with dialkylglycerol instead of diacylglycerol as lipid moiety, GPIb, does not induce TNF␣ production. Moreover, GPIb inhibits the TNF␣ production induced by T. gondii GPI or by GPIa. The core glycan prepared from the two chemically synthesized molecules activates macrophages, showing that the lipid moiety may regulate signaling. Stimulation of macrophages with GPIs of T. gondii results in activation of the transcription factor NF-B, which is inhibited by the chemically synthesized GPIb, suggesting the involvement of NF-B in TNF␣ gene expression. Our results support the idea that T. gondii GPIs are bioactive factors that participate in the production of TNF␣ during toxoplasmal pathogenesis.

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Restriction ofToxoplasma gondiiGrowth in Human Brain Microvascular Endothelial Cells by Activation of Indoleamine 2,3-Dioxygenase

Cited by 115 publications

References 25 publications

Role of Indoleamine-2,3-Dioxygenase in Alpha/Beta and Gamma Interferon-Mediated Antiviral Effects against Herpes Simplex Virus Infections

Role of Indoleamine-2,3-Dioxygenase in Alpha/Beta and Gamma Interferon-Mediated Antiviral Effects against Herpes Simplex Virus Infections

Human bone marrow stromal cells inhibit allogeneic T-cell responses by indoleamine 2,3-dioxygenase–mediated tryptophan degradation

Roles of Glycosylphosphatidylinositols of Toxoplasma gondii

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