Potential Role of Human Brain Microvascular Endothelial Cells in the Pathogenesis of Brain Abscess: Inhibition of Staphylococcus aureus by Activation of Indoleamine 2,3-Dioxygenase

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

doi:10.1055/s-2001-17375

Cited by 57 publications

(44 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Heyes et al (1997a) described IDO activity in human fetal mixed brain cells but without differentiating which cell types express IDO and produce QUIN. Within the human brain, cellular localization of IDO has been found in primary astrocytes, microvascular endothelial cells, microglia, and macrophages Guillemin et al, 2001Guillemin et al, , 2005bSchroten et al, 2001). We previously demonstrated and confirm here that primary human neurons express IDO and that the enzyme is inducible by IFN-␥ (Guillemin et al, 2005b).…”

Section: Discussionmentioning

confidence: 73%

Characterization of the Kynurenine Pathway in Human Neurons

et al. 2007

View full text Add to dashboard Cite

The kynurenine pathway is a major route of L-tryptophan catabolism producing neuroactive metabolites implicated in neurodegeneration and immune tolerance. We characterized the kynurenine pathway in human neurons and the human SK-N-SH neuroblastoma cell line and found that the kynurenine pathway enzymes were variably expressed. Picolinic carboxylase was expressed only in primary and some adult neurons but not in SK-N-SH cells. Because of this difference, SK-N-SH cells were able to produce the excitotoxin quinolinic acid, whereas human neurons produced the neuroprotectant picolinic acid. The net result of kynurenine pathway induction in human neurons is therefore predicted to result in neuroprotection, immune regulation, and tumor inhibition, whereas in SK-N-SH cells, it may result in neurotoxicity, immune tolerance, and tumor promotion. This study represents the first comprehensive characterization of the kynurenine pathway in neurons and the first description of the involvement of the kynurenine pathway as a mechanism for controlling both tumor cell neurotoxicity and persistence.

show abstract

Section: Discussionmentioning

confidence: 73%

Characterization of the Kynurenine Pathway in Human Neurons

et al. 2007

View full text Add to dashboard Cite

show abstract

“…On the basis of our previous identification of IDO as an IFNginducible T-cell inhibitory effector mechanism in human MSCs 2 and recent reports demonstrating antimicrobial activity of IDO expression in specific cell types 13,15 we first investigated, whether pro-inflammatory tissue cytokines such as TNFa and IL1b could induce or enhance IDO expression in human MSCs. As single agents both cytokines failed to stimulate detectable amounts of IDO activity, yet they significantly potentiated IFNginduced IDO activity and this effect was most pronounced with TNFa (Supplementary Figure 1).…”

Section: Resultsmentioning

confidence: 99%

“…Bacterial growth was determined photometrically or via colony counting after 16 h of culture in the absence of any antibiotics 13 while Toxoplasma gondii proliferation in MSC was assessed via parasite-specific uptake of 3 H-uracil during the last 24 h of a 4-day culture period. 14 Moreover, human MSC monolayer cultures were infected with human cytomegalovirus (CMV) at an multiplicity of infection of 0.015 and viral replication was assessed by analysis of CMV genome copy number using quantitative PCR after 3 days of culture.…”

Section: Western Blot Analysis For Human and Murine Ido And Inos Proteinmentioning

confidence: 99%

Human but not murine multipotent mesenchymal stromal cells exhibit broad-spectrum antimicrobial effector function mediated by indoleamine 2,3-dioxygenase

et al. 2011

View full text Add to dashboard Cite

Human multipotent mesenchymal stromal cells (MSCs) exhibit multilineage differentiation potential, support hematopoiesis, and inhibit proliferation and effector function of various immune cells. On the basis of these properties, MSC are currently under clinical investigation in a range of therapeutic applications including tissue repair and immune-mediated disorders such as graft-versus-host-disease refractory to pharmacological immunosuppression. Although initial clinical results appear promising, there are significant concerns that application of MSC might inadvertently suppress antimicrobial immunity with an increased risk of infection. We demonstrate here that on stimulation with inflammatory cytokines human MSC exhibit broad-spectrum antimicrobial effector function directed against a range of clinically relevant bacteria, protozoal parasites and viruses. Moreover, we identify the tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) as the underlying molecular mechanism. We furthermore delineate significant differences between human and murine MSC in that murine MSC fail to express IDO and inhibit bacterial growth. Conversely, only murine but not human MSC express inducible nitric oxide synthase on cytokine stimulation thus challenging the validity of murine in vivo models for the preclinical evaluation of human MSC. Collectively, our data identify human MSC as a cellular immunosuppressant that concurrently exhibits potent antimicrobial effector function thus encouraging their further evaluation in clinical trials.

show abstract

“…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: 97%

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

View full text Add to dashboard Cite

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...

show abstract

Potential Role of Human Brain Microvascular Endothelial Cells in the Pathogenesis of Brain Abscess: Inhibition of Staphylococcus aureus by Activation of Indoleamine 2,3-Dioxygenase

Cited by 57 publications

References 28 publications

Characterization of the Kynurenine Pathway in Human Neurons

Characterization of the Kynurenine Pathway in Human Neurons

Human but not murine multipotent mesenchymal stromal cells exhibit broad-spectrum antimicrobial effector function mediated by indoleamine 2,3-dioxygenase

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

Contact Info

Product

Resources

About