Indoleamine 2, 3-dioxygenase Up-regulates Hypoxia-inducible Factor-1α Expression by Degrading L-tryptophan but Not Its Activity in Human Alloreactive T-cells

  • Theodoros Eleftheriadis Department of Nephrology, Medical School, University of Thessaly, Larissa, Greece http://orcid.org/0000-0001-9302-1633
  • Georgios Pissas Department of Nephrology, Medical School, University of Thessaly, Larissa, Greece
  • Vassilios Liakopoulos Department of Nephrology, Medical School, University of Thessaly, Larissa, Greece
  • Ioannis Stefanidis Department of Nephrology, Medical School, University of Thessaly, Larissa, Greece
Keywords: c-Myc, Hypoxia-inducible factor-1 (HIF-1) α, Indoleamine 2, 3-dioxygenase, Metabolism, p53, T-cell

Abstract

Indoleamine 2, 3-dioxygenase (IDO) suppresses T-cell function at least in part by altering cell metabolism. Hypoxia-inducible factor-1 (HIF-1) increases upon T-cell activation and alters cell metabolism favoring their differentiation to effector cells. The effect of IDO on HIF-1α expression and activity was evaluated. For this purpose, mixed lymphocyte reaction (MLR) was performed using the IDO inhibitor 1-DL-methyl-tryptophan and the p53 inhibitor pifithrin-α. L-tryptophan degradation and cell proliferation were assessed by enzyme-linked immunosorbent assay, whereas the expression of proteins of interest by western blotting. IDO inhibited cell proliferation, and in MLR-derived T-cells increased HIF-1α and p53, whereas it decreased c-Myc. Inhibition of p53 abrogated IDO-induced HIF-1α upregulation. IDO increased the p53 transcriptional targets p21 and TP53-induced glycolysis and apoptosis regulator. The transcriptional targets of both HIF-1α and c-Myc, hexokinase II and lactate dehydrogenase-A were decreased by IDO. Phosphorylated pyruvate dehydrogenase remained unaffected indicating that pyruvate dehydrogenase kinase, a transcriptional target of HIF-1α, is not affected by IDO. In human alloreactive T-cells, IDO up-regulates HIF-1α, by inducing p53 overexpression. However, HIF-1α remains transcriptionally inactive.

References

1. King NJ, Thomas SR. Molecules in focus: Indoleamine 2, 3-dioxygenase. Int J Biochem Cell Biol 2007;39(12):2167-72.2. Curti A, Trabanelli S, Salvestrini V, Baccarani M, Lemoli RM. The role of indoleamine 2,3-dioxygenase in the induction of immune tolerance: Focus on hematology. Blood 2009;113(11):2394-401.3. Eleftheriadis T, Liakopoulos V, Antoniadi G, Stefanidis I, Galaktidou G. Indoleamine 2,3-dioxygenase is increased in hemodialysis patients and affects immune response to hepatitis b vaccination. Vaccine 2011;29(12):2242-7.4. Eleftheriadis T, Yiannaki E, Antoniadi G, Liakopoulos V, Pissas G, Galaktidou G, et al. Plasma indoleamine 2,3-dioxygenase and arginase type i may contribute to decreased blood t-cell count in hemodialysis patients. Ren Fail 2012;34(9):1118-225. Munn DH, Zhou M, Attwood JT, Bondarev I, Conway SJ, Marshall B, et al. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science. 1998;281:1191-3.6. Munn DH, Mellor AL. Indoleamine 2,3-dioxygenase and tumor-induced tolerance. J Clin Invest 2007;117(5):1147-54.7. Eleftheriadis T, Pissas G, Yiannaki E, Markala D, Arampatzis S, Antoniadi G, et al. 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. Hum Immunol 2013;74(12):1501-9.8. Eleftheriadis T, Pissas G, Antoniadi G, Liakopoulos V, Stefanidis I. Indoleamine 2,3-dioxygenase depletes tryptophan, activates general control nonderepressible 2 kinase and downregulates key enzymes involved in fatty acid synthesis in primary human cd4+ t-cells. Immunology 2015;146:292-300.9. Wang R, Dillon CP, Shi LZ, Milasta S, Carter R, Finkelstein D, et al. The transcription factor myc controls metabolic reprogramming upon t lymphocyte activation. Immunity 2011;35(6):871-82.10. Berod L, Friedrich C, Nandan A, Freitag J, Hagemann S, Harmrolfs K, et al. De novo fatty acid synthesis controls the fate between regulatory t and t helper 17 cells. Nat Med 2014;20(11):1327-33.11. Eleftheriadis T, Pissas G, Sounidaki M, Tsogka K, et al. 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. Int J Mol Med2016;38(5):1605-13.12. Michalek RD, Gerriets VA, Jacobs SR, Macintyre AN, MacIver NJ, Mason EF, et al. Cutting edge: Distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory cd4+ t cell subsets. J">https://www.ncbi.nlm.nih.gov/pubmed/?term=Cutting+edge%3A+Distinct+glycolytic+and+lipid+oxidative+metabolic+programs+are+essential+for+effector+and+regulatory+cd4%2B+t+cell+subsets.+Journal+of+immunology.+2011%3B186%3A3299-303">J Immunol 2011;186(6):3299-303.13. Eleftheriadis T, Pissas G, Antoniadi G, Spanoulis A, et al. 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. Int Immunol 2014;26(12):673-84.14. Eleftheriadis T, Pissas G, Antoniadi G, Tsogka K, Sounidaki M, Liakopoulos V, et al. Indoleamine 2,3‑dioxygenase downregulates t cell receptor complex chain and cmyc, and reduces proliferation, lactate dehydrogenase levels and mitochondrial glutaminase in human t cells. Mol">https://www.ncbi.nlm.nih.gov/pubmed/?term=Eleftheriadis+T%2C+Pissas+G%2C+Antoniadi+G%2C+Tsogka+K%2C+Sounidaki+M%2C+Liakopoulos+V%2C+et+al.+Indoleamine+2%2C3%E2%80%91dioxygenase+downregulates+t%E2%80%91cell+receptor+complex+%CE%B6%E2%80%91chain+and+c%E2%80%91myc%2C+and+reduces+proliferation%2C+lactate+dehydrogenase+levels+and+mitochondrial+glutaminase+in+human+t%E2%80%91cells.">Mol Med Rep2016;13(1):925-32.15. Brady CA, Attardi LD. P53 at a glance. J Cell Sci. 2010;123:2527-32.16. Miller DM, Thomas SD, Islam A, Muench D, Sedoris K. C-myc and cancer metabolism. Clin Cancer Res 2012;18:5546-53.17. Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, et al. Targeting of hif-alpha to the von hippel-lindau ubiquitylation complex by o2-regulated prolyl hydroxylation. Science 2001;292(5516):468-72.18. Pan F, Barbi J, Pardoll DM. Hypoxia-inducible factor 1: A link between metabolism and t cell differentiation and a potential therapeutic target. Oncoimmunology 2012;1(4):510-5.19. Dang EV, Barbi J, Yang HY, Jinasena D, Yu H, Zheng Y, et al. Control of t(h)17/t(reg) balance by hypoxia-inducible factor 1. Cell 2011;146(5):772-84.20. Shi LZ, Wang R, Huang G, Vogel P, Neale G, Green DR, et al. Hif1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of th17 and treg cells. J Exp Med 2011;208(7):1367-76.21. Clambey ET, McNamee EN, Westrich JA, Glover LE, Campbell EL, Jedlicka P, et al. Hypoxia-inducible factor-1 alpha-dependent induction of foxp3 drives regulatory t-cell abundance and function during inflammatory hypoxia of the mucosa. Proc Natl Acad Sci U S A 2012;109(41):E2784-93.22. Munn DH, Sharma MD, Baban B, Harding HP, Zhang Y, Ron D, et al. Gcn2 kinase in t cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. Immunity 2005;22(5):633-42.23. Eleftheriadis T, Pissas G, Antoniadi G, Liakopoulos V, Stefanidis I. 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. Immunology 2015;146(2):292-300.24. Komarov PG, Komarova EA, Kondratov RV, Christov-Tselkov K, Coon JS, Chernov MV, et al. A chemical inhibitor of p53 that protects mice from the side effects of cancer therapy. Science 1999; 285(5434):1733-7.25. Sermeus A, Michiels C. Reciprocal influence of the p53 and the hypoxic pathways. Cell Death Dis 2011;2:e164.26. Sutton TA, Wilkinson J, Mang HE, Knipe NL, Plotkin Z, Hosein M, et al. P53 regulates renal expression of hif-1{alpha} and pvhl under physiological conditions and after ischemia-reperfusion injury. Am J Physiol Renal Physiol 2008;295(6):F1666-77.27. Nieminen AL, Qanungo S, Schneider EA, Jiang BH, Agani FH. Mdm2 and hif-1alpha interaction in tumor cells during hypoxia. J Cell Physiol 2005;204(2):364-9.28. Kaluz S, Kaluzova M, Stanbridge EJ. Does inhibition of degradation of hypoxia-inducible factor (hif) alpha always lead to activation of hif? Lessons learnt from the effect of proteasomal inhibition on hif activity. J Cell Biochem 2008;104(2):536-544.29. Bensaad K, Tsuruta A, Selak MA, Vidal MN, Nakano K, Bartrons R, et al. Tigar, a p53-inducible regulator of glycolysis and apoptosis. Cell 2006;126(1):107-20.30. Iyer NV, Kotch LE, Agani F, Leung SW, Laughner E, Wenger RH, et al. Cellular and developmental control of o2 homeostasis by hypoxia-inducible factor 1 alpha. Genes Dev 1998;12(2):149-62.31. Valera A, Pujol A, Gregori X, Riu E, Visa J, Bosch F. Evidence from transgenic mice that myc regulates hepatic glycolysis. Faseb J 1995;9(11):1067-78.32. Kim JW, Tchernyshyov I, Semenza GL, Dang CV. Hif-1-mediated expression of pyruvate dehydrogenase kinase: A metabolic switch required for cellular adaptation to hypoxia. Cell Metab 2006;3(3):177-85.33. Schmid T, Zhou J, Kohl R, Brune B. P300 relieves p53-evoked transcriptional repression of hypoxia-inducible factor-1 (hif-1). Biochem J 2004;380(pt 1):289-95.34. Datta K, Li J, Bhattacharya R, Gasparian L, Wang E, Mukhopadhyay D. Protein kinase c zeta transactivates hypoxia-inducible factor alpha by promoting its association with p300 in renal cancer. Cancer Res 2004;64(2):456-62.35. Vorrink SU, Domann FE. Regulatory crosstalk and interference between the xenobiotic and hypoxia sensing pathways at the ahr-arnt-hif1alpha signaling node. Chem Biol Interact 2014;218:82-8.36. Eleftheriadis T, Pissas G, Antoniadi G, Liakopoulos V, Stefanidis I. Kynurenine, by activating aryl hydrocarbon receptor, decreases erythropoietin and increases hepcidin production in hepg2 cells: A new mechanism for anemia of inflammation. Exp Hematol 2016;44(1):60-67 e61.37. Mezrich JD, Fechner JH, Zhang X, Johnson BP, Burlingham WJ, Bradfield CA. An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory t cells. J Immunol 2010;185(6):3190-8.

Published
2018-02-26
How to Cite
1.
Eleftheriadis T, Pissas G, Liakopoulos V, Stefanidis I. Indoleamine 2, 3-dioxygenase Up-regulates Hypoxia-inducible Factor-1α Expression by Degrading L-tryptophan but Not Its Activity in Human Alloreactive T-cells. ijaai. 17(1):56-7.
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Original Article(s)