The Indoleamine 2,3-dioxygenase Inhibitor 1-methyl-tryptophan Suppresses Mitochondrial Function, Induces Aerobic Glycolysis and Decreases Interleukin-10 Production in Human Lymphocytes

Eleftheriadis, Theodoros; Pissas, Georgios; Karioti, Aggeliki; Antoniadi, Georgia; Liakopoulos, Vassilios; Dafopoulou, Konstantina; Pournaras, Spyros; Koukoulis, Georgios; Stefanidis, Ioannis

doi:10.3109/08820139.2012.682244

Cited by 19 publications

(9 citation statements)

References 38 publications

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“…Tregs suppress activation of liver NKTs in an IL10‐dependent manner . Intravenously injected IDO induces the production of immunosuppressive IL10 in activated lymphocytes, whereas 1‐MT significantly reduces capacity of stimulated lymphocytes to secrete IL10 . Because MSCs, in a paracrine manner, significantly increased the capacity of Tregs to produce immunosuppressive IL10 and that this phenomenon was abrogated by 1‐MT (Fig.…”

Section: Discussionmentioning

confidence: 85%

“…(50) Intravenously injected IDO induces the production of immunosuppressive IL10 in activated lymphocytes, whereas 1-MT significantly reduces capacity of stimulated lymphocytes to secrete IL10. (51) Because MSCs, in a paracrine manner, significantly increased the capacity of Tregs to produce immunosuppressive IL10 and that this phenomenon was abrogated by 1-MT (Fig. 4F), we propose that MSCs, through the production of IDO, induced increased production of IL10 in Tregs, which in turn, in an IL10-dependent manner, attenuated hepatotoxicity of liver NKTs, resulting in the attenuation of acute liver failure (Fig.…”

Section: Discussionmentioning

confidence: 90%

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Crosstalk between mesenchymal stem cells and T regulatory cells is crucially important for the attenuation of acute liver injury

et al. 2018

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One of the therapeutic options for the treatment of fulminant hepatitis is repopulation of intrahepatic regulatory cells because their pool is significantly reduced during acute liver failure. Although it is known that mesenchymal stem cells (MSCs), which have beneficent effects in the therapy of fulminant hepatitis, may promote expansion of regulatory T cells (Tregs) and regulatory B cells (Bregs), the role of these regulatory cells in MSC-mediated attenuation of acute liver injury is unknown. Herewith, we described the molecular mechanisms involved in the crosstalk between MSCs and liver regulatory cells and analyzed the potential of MSC-based therapy for the expansion of intrahepatic regulatory cells in mouse model of acute liver failure. MSC-dependent attenuation of α-galactosylceramide (α-GalCer)-induced acute liver injury in mice was accompanied with an increased presence of interleukin (IL) 10-producing CD4 CD25 forkhead box P3 Tregs and IL10- and transforming growth factor β-producing marginal zone-like Bregs in the liver. Depletion of Bregs did not alter MSC-based alleviation of acute liver failure, whereas depletion of Tregs completely abrogated hepatoprotective effects of MSCs and inhibited their capacity to attenuate hepatotoxicity of liver natural killer T cells (NKTs), indicating that Tregs, and not Bregs, were critically involved in MSC-based modulation of acute liver inflammation. MSCs, in a paracrine, indoleamine 2,3-dioxygenase-dependent manner, significantly increased the capacity of Tregs to produce immunosuppressive IL10 and to suppress hepatotoxicity of liver NKTs. Accordingly, adoptive transfer of MSC-primed Tregs resulted in the complete attenuation of α-GalCer-induced acute liver failure. In conclusion, our findings highlighted the crucial importance of Tregs for MSC-based attenuation of acute liver failure and indicated the significance of MSC-mediated priming of Tregs as a new therapeutic approach in Treg-based therapy of acute liver injury. Liver Transplantation 24 687-702 2018 AASLD.

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Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 90%

Crosstalk between mesenchymal stem cells and T regulatory cells is crucially important for the attenuation of acute liver injury

et al. 2018

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“…Cytokine correlations with the kynurenine to tryptophan ratio have been demonstrated in other disorders, such as cancer [33], meningitis [34], and atherosclerosis [35]. Activation of IDO induces the production of IL-10 [36, 37], which is a well characterized CNS response in HAT, while IL-10 has in turn been reported to inhibit the IFN-γ–induced activation of IDO in neurons [38]. This may reflect a novel mechanism by which coordination of the kynurenine pathway and inflammatory/counterinflammaotry regulation influence neuropathogenesis in HAT [32].…”

Section: Discussionmentioning

confidence: 99%

Kynurenine Pathway Activation in Human African Trypanosomiasis

Sternberg¹,

Forrest²,

Dalton

et al. 2016

INFDIS

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Background.The kynurenine pathway of tryptophan oxidation is associated with central nervous system (CNS) inflammatory pathways. Inhibition of this pathway ameliorates CNS inflammation in rodent models of the late (meningoencephalitic) stage of human African trypanosomiasis (HAT). In this study, we evaluate whether the kynurenine pathway is activated in clinical HAT and associated with CNS inflammatory responses.Methods.We measured cerebrospinal fluid (CSF) tryptophan and kynurenine metabolite concentrations in patients infected with Trypanosoma brucei rhodesiense, using liquid chromatography–mass spectrometry.Results.Kynurenine concentration in CSF was increased in both the early and late stages of disease, with a progressive increase in tryptophan oxidation associated with stage progression. Kynurenine pathway activation was associated with increases in neuroinflammatory markers, but there was no clear relationship to neurological symptoms.Conclusions.CNS kynurenine pathway activation occurs during HAT, including cases prior to the current diagnostic cutoff for late-stage infection, providing evidence for early CNS involvement in HAT. Metabolite data demonstrate that the kynurenine-3-monooxygenase and kynurenine aminotransferase branches of the kynurenine pathway are active. The association between tryptophan oxidation and CNS inflammatory responses as measured by CSF interleukin 6 (IL-6) concentration supports a role of kynurenine metabolites in the inflammatory pathogenesis of late-stage HAT.

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“…The PDH dehydrogenase regulates the influx of pyruvate into the mitochondria, increasing the ratio of glucose oxidation to glycolysis. Notably, indoleamine 2,3-dioxygenase, a key immunomodulatory enzyme, exerts its suppressive effect at least in part by inhibiting aerobic glycolysis and glutaminolysis in activated T cells (6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

Malate dehydrogenase-2 inhibitor LW6 promotes metabolic adaptations and reduces proliferation and apoptosis in activated human T-cells

Eleftheriadis

Pissas

Antoniadi

et al. 2015

Experimental and Therapeutic Medicine

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Activated T cells rely on aerobic glycolysis and glutaminolysis in order to proliferate and differentiate into effector cells. Therefore, intervention in these metabolic pathways inhibits proliferation. The aim of the present study was to evaluate the effects of Krebs' cycle inhibition at the level of malate dehydrogenase-2 (MDH2) in human activated T cells using the MDH2 inhibitor LW6. Activated T cells from healthy volunteers were cultured in the presence or absence of LW6 and cytotoxicity, cell proliferation and the expression levels of hypoxia-inducible factor (HIF)-1α, c-Myc, p53, cleaved caspase-3 and certain enzymes involved in glucose metabolism and glutaminolysis were evaluated. The results revealed that LW6 was not toxic and decreased apoptosis and the levels of the pro-apoptotic tumor suppressor p53. In addition, LW6 inhibited T-cell proliferation and decreased the levels of c-Myc, HIF-1α, glucose transporter-1, hexokinase-II, lactate dehydrogenase-A and phosphorylated pyruvate dehydrogenase. By contrast, LW6 increased the levels of pyruvate dehydrogenase. These alterations may lead to decreased production of pyruvate, which preferentially enters into the Krebs' cycle. Furthermore, LW6 decreased the levels of glutaminase-2, while increasing those of glutaminase-1, which may preserve glutaminolysis, and possibly pyruvate-malate cycling, potentially protecting the cells from energy collapse. In summary, the inhibition of MDH2 in activated T cells abrogates proliferation without adversely affecting cell survival. Adaptations of cellular glucose and glutamine metabolism may prevent energy collapse.

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The Indoleamine 2,3-dioxygenase Inhibitor 1-methyl-tryptophan Suppresses Mitochondrial Function, Induces Aerobic Glycolysis and Decreases Interleukin-10 Production in Human Lymphocytes

Abstract: Considering that cell metabolism plays a significant role in lymphocyte differentiation and function, IDO may exert its immunomodulatory effect by interfering with cell metabolism.

Cited by 19 publications

References 38 publications

Crosstalk between mesenchymal stem cells and T regulatory cells is crucially important for the attenuation of acute liver injury

Crosstalk between mesenchymal stem cells and T regulatory cells is crucially important for the attenuation of acute liver injury

Kynurenine Pathway Activation in Human African Trypanosomiasis

Malate dehydrogenase-2 inhibitor LW6 promotes metabolic adaptations and reduces proliferation and apoptosis in activated human T-cells

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