title: Indoleamine 2,3-dioxygenase increases p53 levels in alloreactive human T cells, and both indoleamine 2,3-dioxygenase and p53 suppress glucose uptake, glycolysis and proliferation.
abstract: Indoleamine 2,3-dioxygenase (IDO) suppresses adaptive immunity by inhibiting T-cell proliferation and altering glucose metabolism. The tumor suppressor p53 also alters these cellular processes with similar results. The effect of IDO on p53 and on glucose metabolism was evaluated in alloreactive T cells. Mixed-lymphocyte reactions (MLRs) were performed in the presence or not of the IDO inhibitor, 1-dl-methyl-tryptophan (1-MT) and/or the p53 inhibitor, pifithrin-α (PFT). Cell proliferation, glucose consumption and lactate production were assessed. 1-MT increased cell proliferation, glucose influx and lactate production, whereas PFT enhanced cell proliferation and glucose influx, leaving lactate production unaffected. In MLR-derived T cells, protein analysis revealed that IDO activated general control non-derepressible 2 kinase and induced p53, p-p53 (p53 phosphorylated at serine 15) and p21. In addition, both IDO and p53 decreased glucose transporter 1 and TP53-induced glycolysis and apoptosis regulator and increased synthesis of cytochrome c oxidase 2. IDO also reduced lactate dehydrogenase-A and glutaminase 2 levels, whereas p53 left them unaffected. Neither 1-MT nor PFT affected glucose-6-phosphate dehydrogenase. In conclusion, in alloreactive T cells, IDO increases p53 levels, and both IDO and p53 inhibit cell proliferation, glucose consumption and glycolysis. Lactate production and glutaminolysis are also suppressed by IDO, but not by p53.
authors: Department of Nephrology, Medical School, University of Thessaly, Neo Ktirio, Mezourlo Hill, 41110 Larissa, Greece teleftheriadis@yahoo.com.
authors: Theodoros
authors: T
authors: Eleftheriadis
authors: Department of Nephrology, Medical School, University of Thessaly, Neo Ktirio, Mezourlo Hill, 41110 Larissa, Greece.
authors: Georgios
authors: G
authors: Pissas
authors: Department of Nephrology, Medical School, University of Thessaly, Neo Ktirio, Mezourlo Hill, 41110 Larissa, Greece.
authors: Georgia
authors: G
authors: Antoniadi
authors: Department of Nephrology, Medical School, University of Thessaly, Neo Ktirio, Mezourlo Hill, 41110 Larissa, Greece.
authors: Aginor
authors: A
authors: Spanoulis
authors: Department of Nephrology, Medical School, University of Thessaly, Neo Ktirio, Mezourlo Hill, 41110 Larissa, Greece.
authors: Vassilios
authors: V
authors: Liakopoulos
authors: Department of Nephrology, Medical School, University of Thessaly, Neo Ktirio, Mezourlo Hill, 41110 Larissa, Greece.
authors: Ioannis
authors: I
authors: Stefanidis
mesh_terms: D000328:Adult; D051017:Apoptosis Regulatory Proteins; D052160:Benzothiazoles / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004789:Enzyme Activation; D005260:Female; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D005954:Glucosephosphate Dehydrogenase / Q000378:metabolism; D006019:Glycolysis; D064368:Healthy Volunteers; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D000080864:Lactate Dehydrogenase 5; D019344:Lactic Acid / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D008875:Middle Aged; D024101:Mitochondrial Proteins / Q000378:metabolism; D018832:Molecular Chaperones; D046912:Multiprotein Complexes / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014050:Toluene / Q000031:analogs & derivatives / Q000494:pharmacology; D014364:Tryptophan / Q000031:analogs & derivatives / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D052160:Benzothiazoles; D002352:Carrier Proteins; D051272:Glucose Transporter Type 1; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones; D046912:Multiprotein Complexes; C400285:SCO2 protein, human; D016159:Tumor Suppressor Protein p53; D019344:Lactic Acid; D014050:Toluene; D014364:Tryptophan; C121565:pifithrin; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5; D005954:Glucosephosphate Dehydrogenase; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D010744:Phosphoric Monoester Hydrolases; C512708:TIGAR protein, human; D005947:Glucose; C525396:1-methyltryptophan
keywords: 3-dioxygenase; GCN2 kinase; T cells; aerobic glycolysis; glutaminolysis; indoleamine 2; p53; proliferation