title: 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.
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.
authors.affiliation: Department of Nephrology, Medical School, University of Thessaly, Larissa 41110, Greece.
authors.forename: Theodoros
authors.initials: T
authors.lastname: Eleftheriadis
authors.affiliation: Department of Nephrology, Medical School, University of Thessaly, Larissa 41110, Greece.
authors.forename: Georgios
authors.initials: G
authors.lastname: Pissas
authors.affiliation: Department of Nephrology, Medical School, University of Thessaly, Larissa 41110, Greece.
authors.forename: Georgia
authors.initials: G
authors.lastname: Antoniadi
authors.affiliation: Department of Nephrology, Medical School, University of Thessaly, Larissa 41110, Greece.
authors.forename: Konstantina
authors.initials: K
authors.lastname: Tsogka
authors.affiliation: Department of Nephrology, Medical School, University of Thessaly, Larissa 41110, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Sounidaki
authors.affiliation: Department of Nephrology, Medical School, University of Thessaly, Larissa 41110, Greece.
authors.forename: Vassilios
authors.initials: V
authors.lastname: Liakopoulos
authors.affiliation: Department of Nephrology, Medical School, University of Thessaly, Larissa 41110, Greece.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Stefanidis
mesh_terms: D049109:Cell Proliferation / Q000235:genetics; D005972:Glutaminase / Q000096:biosynthesis* / Q000235:genetics; D006019:Glycolysis / Q000235:genetics; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000096:biosynthesis / Q000235:genetics*; D007770:L-Lactate Dehydrogenase / Q000096:biosynthesis* / Q000235:genetics; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis* / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis* / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000235:genetics; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis; D054462:p21-Activated Kinases / Q000096:biosynthesis
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D016271:Proto-Oncogene Proteins c-myc; D011948:Receptors, Antigen, T-Cell; D016159:Tumor Suppressor Protein p53; D007770:L-Lactate Dehydrogenase; C529271:EIF2AK4 protein, human; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; C586504:GLS2 protein, human; D005972:Glutaminase