indoleamine 2, 3dioxygenase upregulates hypoxiainducible factor1α expression by degrading ltryptophan but not its activity in human alloreactive tcells

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.