Indoleamine 2,3‑dioxygenase downregulates T‑cell receptor complex ζ‑chain and c‑Myc, and reduces proliferation, lactate dehydrogenase levels and mitochondrial glutaminase in human T‑cells

Eleftheriadis,Theodoros; Pissas,Georgios; Antoniadi,Georgia; Tsogka,Konstantina; Sounidaki,Maria; Liakopoulos,Vassilios; Stefanidis,Ioannis

doi:10.3892/mmr.2015.4595

Indoleamine 2,3‑dioxygenase downregulates T‑cell receptor complex ζ‑chain and c‑Myc, and reduces proliferation, lactate dehydrogenase levels and mitochondrial glutaminase in human T‑cells

Authors:
- Theodoros Eleftheriadis
- Georgios Pissas
- Georgia Antoniadi
- Konstantina Tsogka
- Maria Sounidaki
- Vassilios Liakopoulos
- Ioannis Stefanidis
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Affiliations: Department of Nephrology, Medical School, University of Thessaly, Larissa 41110, Greece
Published online on: November 20, 2015 https://doi.org/10.3892/mmr.2015.4595
Pages: 925-932

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Abstract

Indoleamine 2,3‑dioxygenase (IDO), through L‑tryptophan depletion, activates general control non‑derepressible (GCN) 2 kinase and suppresses T‑cell proliferation, in addition to suppressing aerobic glycolysis and glutaminolysis, which are required for these rapidly proliferating cells. A number of, however not all of these alterations, are partially mediated through IDO‑induced p53 upregulation. In two‑way mixed lymphocyte reactions (MLRs), IDO reduced cellular proliferation. In MLR‑derived T‑cells, IDO induced the expression levels of p53 and p21, however concurrently reduced the levels of ζ‑chain, c‑Myc, lactate dehydrogenase A (LDH‑A) and glutaminase (GLS)2. However, p53 had no effect on the expression of the above proteins. These results were recapitulated in T‑cells activated with anti‑CD2, anti‑CD3 and anti‑CD28 by direct activation of the GCN2 kinase with tryptophanol. In conclusion, IDO, through GCN2 kinase activation, downregulates the levels of TCR‑complex ζ‑chain and c‑Myc, resulting in the suppression of T‑cell proliferation and a reduction in the levels of LDH‑A and GLS2, which are key enzymes involved in aerobic glycolysis and glutaminolysis, respectively.

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