Indoleamine 2,3-dioxygenase, by degrading L-tryptophan, enhances carnitine palmitoyltransferase I activity and fatty acid oxidation, and exerts fatty acid-dependent effects in human alloreactive CD4+ T-cells.
Indoleamine 2,3-dioxygenase (IDO) is expressed in antigen-presenting cells and by degrading L-tryptophan along the kynurenine pathway suppresses CD4+ T-cell proliferation, induces apoptosis and promotes differentiation towards a regulatory as opposed to an effector phenotype. Recent findings revealed that the above effects may be mediated through alterations in T-cell metabolism. In this study, the effect of IDO on fatty acid β-oxidation in CD4+ T-cells was evaluated in human mixed lymphocyte reactions (MLRs) using the IDO inhibitor, 1-DL-methyl-tryptophan. Protein analysis of CD4+ T-cells isolated from the MLR showed that L-tryptophan degradation acts by activating the general control non‑derepressible 2 kinase and aryl-hydrocarbon receptor in T-cells. In the absence of IDO inhibition, fatty acid oxidation increased along with increased activity of carnitine palmitoyltransferase I (CPT1), the latter due to the increased expression of CPT1 isoenzymes and alterations in acetyl-CoA carboxylase 2, the enzyme that controls CPT1 activity. Increased fatty acid oxidation due to the action of IDO was accompanied by an increased expression of forkhead box P3 (FoxP3) and a decreased expression of related orphan receptor γt (RORγt), the signature transcription factors of regulatory T-cells and T helper 17 cells, respectively. However, in MLR and in the presence of fatty acid in the culture medium, IDO did not inhibit proliferation. Additionally, fatty acid protected the CD4+ T-cells against apoptosis. Thus, IDO, by degrading L-tryptophan, enhances CPT1 activity and fatty acid oxidation, and exerts fatty acid-dependent effects in human alloreactive CD4+ T-cells.
Department of Nephrology, Medical School, University of Thessaly, Larissa, Greece.
Theodoros
T
Eleftheriadis
Department of Nephrology, Medical School, University of Thessaly, Larissa, Greece.
Georgios
G
Pissas
Department of Nephrology, Medical School, University of Thessaly, Larissa, Greece.
Maria
M
Sounidaki
Department of Nephrology, Medical School, University of Thessaly, Larissa, Greece.
Konstantina
K
Tsogka
Organ Transplant Unit, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece.
Nikolaos
N
Antoniadis
Department of Nephrology, Medical School, University of Thessaly, Larissa, Greece.
Georgia
G
Antoniadi
Department of Nephrology, Medical School, University of Thessaly, Larissa, Greece.
Vassilios
V
Liakopoulos
Department of Nephrology, Medical School, University of Thessaly, Larissa, Greece.
Ioannis
I
Stefanidis
D000328:Adult; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism*; D002478:Cells, Cultured; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D008297:Male; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000378:metabolism; D014364:Tryptophan / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D019892:eIF-2 Kinase / Q000378:metabolism
C418974:FOXP3 protein, human; D005227:Fatty Acids; D051858:Forkhead Transcription Factors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D014364:Tryptophan; D002334:Carnitine O-Palmitoyltransferase; C583541:EIF2AK1 protein, human; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase; C531557:eIF2alpha kinase, mouse; C525396:1-methyltryptophan