Inhibition of indoleamine 2,3-dioxygenase in mixed lymphocyte reaction affects glucose influx and enzymes involved in aerobic glycolysis and glutaminolysis in alloreactive T-cells

Eleftheriadis, Theodoros; Pissas, Georgios; Yiannaki, E.; Markala, Dimitra; Arampatzis, Spyridon; Antoniadi, Georgia; Liakopoulos, Vassilios; Stefanidis, Ioannis

doi:10.1016/j.humimm.2013.08.268

Cited by 26 publications

(39 citation statements)

References 42 publications

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“…The above findings therefore indicate that IDO1-catalysed LTrp depletion, the synthesis of Kyn pathway metabolites and the activation of AhR and other signalling pathways control the activation status, phenotype and viability of T-cells, B-cells and NK cells in various ways including: (i) induction of cell cycle arrest in T-cells and induction of cell death in T-cells, B-cells and NK cells [51,[229][230][231], (ii) impairment of NK cell-mediated killing by preventing the up-regulation of the activating receptors NKp46 and NKG2D [115], (iii) Th2 polarisation of invariant NKT cells [237], (iv) apoptosis of Th1 cells but not Th2 cells [238], (v) interfering with glucose metabolism in effector T-cells to inhibit proliferation [239,240], (vi) defective TCR activation via the interruption of Ca 2+ signalling [241], (vii) down-regulation of the ζ -chain in the TCR complex on CD8 + T-cells [232], (viii) acquisition and maintenance of an immunosuppressive Foxp3 + Treg (rather than a pro-inflammatory Th17) phenotype by naïve CD4 + T-cells [232,[242][243][244] involving the IDO1-and Kyn/AhRdependent blockade of the down-regulation of the Eos transcription factor (necessary for reprogramming of Tregs into Th17 inflammatory helper-like cells) [245], and (ix) direct activation of the suppressor activity of Foxp3 + Tregs involving the PD-1 (programmed cell death 1)/PD-L (programmed cell death ligand) pathway [226].…”

Section: Lymphocytesmentioning

confidence: 99%

Role of indoleamine 2,3-dioxygenase in health and disease

et al. 2015

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IDO1 (indoleamine 2,3-dioxygenase 1) is a member of a unique class of mammalian haem dioxygenases that catalyse the oxidative catabolism of the least-abundant essential amino acid, L-Trp (L-tryptophan), along the kynurenine pathway. Significant increases in knowledge have been recently gained with respect to understanding the fundamental biochemistry of IDO1 including its catalytic reaction mechanism, the scope of enzyme reactions it catalyses, the biochemical mechanisms controlling IDO1 expression and enzyme activity, and the discovery of enzyme inhibitors. Major advances in understanding the roles of IDO1 in physiology and disease have also been realised. IDO1 is recognised as a prominent immune regulatory enzyme capable of modulating immune cell activation status and phenotype via several molecular mechanisms including enzyme-dependent deprivation of L-Trp and its conversion into the aryl hydrocarbon receptor ligand kynurenine and other bioactive kynurenine pathway metabolites, or non-enzymatic cell signalling actions involving tyrosine phosphorylation of IDO1. Through these different modes of biochemical signalling, IDO1 regulates certain physiological functions (e.g. pregnancy) and modulates the pathogenesis and severity of diverse conditions including chronic inflammation, infectious disease, allergic and autoimmune disorders, transplantation, neuropathology and cancer. In the present review, we detail the current understanding of IDO1's catalytic actions and the biochemical mechanisms regulating IDO1 expression and activity. We also discuss the biological functions of IDO1 with a focus on the enzyme's immune-modulatory function, its medical implications in diverse pathological settings and its utility as a therapeutic target.

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Section: Lymphocytesmentioning

confidence: 99%

Role of indoleamine 2,3-dioxygenase in health and disease

et al. 2015

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“…For instance, CD4 + effector T-cells (Teff) express high levels of the glucose transporter GLUT1 and are reliant on glucose metabolism, whereas regulatory T-cells (Tregs) express low levels of GLUT1 and are reliant on lipid oxidation (6). Notably, the key immunomodulatory enzyme indoleamine 2,3-dioxyganase exerts its immunosuppressive effects at least in part by affecting glucose metabolism in T-cells (7,8).…”

Section: Introductionmentioning

confidence: 99%

In human alloreactive CD4+ T-cells, dichloroacetate inhibits aerobic glycolysis, induces apoptosis and favors differentiation towards the regulatory T-cell subset instead of effector T-cell subsets

Eleftheriadis

Sounidaki

Pissas

et al. 2016

Molecular Medicine Reports

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Although kidney transplantation is the best therapy for end-stage renal disease, rejection remains a concern, and currently available immunosuppressive agents contribute to morbidity and mortality. Thus, novel immunosuppressive drugs are required. Dichloroacetate (DCA) is already used in the treatment of congenital lactic acidosis and characterized by limited toxicity. As DCA inhibits aerobic glycolysis, which is a prerequisite for CD4+ T-cell proliferation and differentiation into effector T-cells, its possible immunosuppressive role in mixed lymphocyte reaction (MLR), a model of alloreactivity, was investigated. Glucose and lactate concentrations were measured in the supernatants, and cell proliferation was assessed immunoenzymatically. CD4+ T‑cells were then isolated from the MLRs and the expression of cleaved caspase‑3, various enzymes involved in glycolysis, and the signature transcription factors of CD4+ T‑cell subsets were evaluated by western blotting. In MLRs, DCA decreased glucose consumption and aerobic glycolysis, while it exerted a negligible effect on cell proliferation. In CD4+ T‑cells, DCA induced apoptosis, and decreased the expression of glucose trasporter‑1, hexokinase II, lactate dehydrogenase‑A and phosphorylated pyruvate dehydrogenase, while it increased total pyruvate dehydrogenase. In addition, DCA increased the expression of transcription factor forkhead box P3, whereas it decreased the expression of T‑box transcription factor TBX21, trans‑acting T-cell-specific transcription factor GATA‑3 and retinoic acid receptor related orphan receptor‑γt. In conclusion, in alloreactive CD4+ T‑cells, DCA inhibits aerobic glycolysis, induces apoptosis and favors differentiation towards the regulatory T‑cell subset. These characteristics render it a promising immunosuppressive agent in the field of transplantation.

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“…Indoleamine 2,3‐dioxygenase decreases glucose influx in activated human T cells and inhibits aerobic glycolysis by affecting the expression of glucose transporter 1 and various glycolytic enzymes . However, the effect of IDO on FA synthesis upon T‐cell activation has not been evaluated.…”

Section: Introductionmentioning

confidence: 99%

Indoleamine 2,3‐dioxygenase depletes tryptophan, activates general control non‐derepressible 2 kinase and down‐regulates key enzymes involved in fatty acid synthesis in primary human CD4⁺ T cells

et al. 2015

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Indoleamine 2,3-dioxygenase (IDO) is expressed in antigen-presenting cells and exerts immunosuppressive effects on CD4(+) T cells. One mechanism is through the inhibition of aerobic glycolysis. Another prerequisite for T-cell proliferation and differentiation into effector cells is increased fatty acid (FA) synthesis. The effect of IDO on enzymes involved in FA synthesis was evaluated in primary human cells both in mixed lymphocyte reactions in the presence or not of the IDO inhibitor 1-dl-methyl-tryptophan, and in stimulated CD4(+) T cells in the presence or not of the general control non-derepressible 2 (GCN2) kinase activator tryptophanol (TRP). IDO or TRP inhibited cell proliferation. By assessing the level of GCN2 kinase or mammalian target of rapamycin complex 1 substrates along with a kynurenine free system we showed that IDO exerts its effect mainly through activation of GCN2 kinase. IDO or TRP down-regulated ATP-citrate lyase and acetyl coenzyme A carboxylase 1, key enzymes involved in FA synthesis. Also, IDO or TRP altered the expression of enzymes that control the availability of carbon atoms for FA synthesis, such as lactate dehydrogenase-A, pyruvate dehydrogenase, glutaminase 1 and glutaminase 2, in a way that inhibits FA synthesis. In conclusion, IDO through GCN2 kinase activation inhibits CD4(+) T-cell proliferation and down-regulates key enzymes that directly or indirectly promote FA synthesis, a prerequisite for CD4(+) T-cell proliferation and differentiation into effector cell lineages.

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Inhibition of indoleamine 2,3-dioxygenase in mixed lymphocyte reaction affects glucose influx and enzymes involved in aerobic glycolysis and glutaminolysis in alloreactive T-cells

Cited by 26 publications

References 42 publications

Role of indoleamine 2,3-dioxygenase in health and disease

Role of indoleamine 2,3-dioxygenase in health and disease

In human alloreactive CD4+ T-cells, dichloroacetate inhibits aerobic glycolysis, induces apoptosis and favors differentiation towards the regulatory T-cell subset instead of effector T-cell subsets

Indoleamine 2,3‐dioxygenase depletes tryptophan, activates general control non‐derepressible 2 kinase and down‐regulates key enzymes involved in fatty acid synthesis in primary human CD4⁺ T cells

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Inhibition of indoleamine 2,3-dioxygenase in mixed lymphocyte reaction affects glucose influx and enzymes involved in aerobic glycolysis and glutaminolysis in alloreactive T-cells

Cited by 26 publications

References 42 publications

Role of indoleamine 2,3-dioxygenase in health and disease

Role of indoleamine 2,3-dioxygenase in health and disease

In human alloreactive CD4+ T-cells, dichloroacetate inhibits aerobic glycolysis, induces apoptosis and favors differentiation towards the regulatory T-cell subset instead of effector T-cell subsets

Indoleamine 2,3‐dioxygenase depletes tryptophan, activates general control non‐derepressible 2 kinase and down‐regulates key enzymes involved in fatty acid synthesis in primary human CD4+ T cells

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Indoleamine 2,3‐dioxygenase depletes tryptophan, activates general control non‐derepressible 2 kinase and down‐regulates key enzymes involved in fatty acid synthesis in primary human CD4⁺ T cells