Alternative titles; symbols
HGNC Approved Gene Symbol: IDO1
Cytogenetic location: 8p11.21 Genomic coordinates (GRCh38): 8:39,913,891-39,928,790 (from NCBI)
Gamma-interferon (IFNG; 147570) has an antiproliferative effect on many tumor cells and inhibits intracellular pathogens such as Toxoplasma and Chlamydia, at least partly because of the induction of indoleamine 2,3-dioxygenase (INDO; EC 1.13.11.52). This enzyme catalyzes the degradation of the essential amino acid L-tryptophan to N-formyl-kynurenine.
Dai and Gupta (1990) isolated a cDNA clone corresponding to an IFNG-inducible mRNA, determined its nucleotide sequence, and identified its protein product as INDO.
Using quantitative RT-PCR and Western blot analyses, Spinelli et al. (2019) showed that Ido1 was exclusively expressed in placenta and absent in embryo during early mouse development. Ido1 expression started at embryonic day 7.5 (E7.5), peaked at E9.5, and was reduced afterward. Allele-specific transcription analysis revealed that the Ido1 locus was imprinted and that both of its 2 variants were transcribed from the maternal allele.
Using an INDO cDNA as a probe, Kadoya et al. (1992) isolated genomic DNA clones and determined their restriction maps and partial nucleotide sequences. The human gene spans 15 kb with 10 exons. The 5-prime terminus of the INDO mRNA is 33 nucleotides upstream of the translation initiation codon ATG. Southern blot analysis indicated that the INDO gene is present in single copy.
By analyzing a series of human/Chinese hamster cell hybrids for the presence of the human IDO gene by PCR and Southern blot analysis, Burkin et al. (1993) determined that the gene is located in the pericentromeric region of human chromosome 8, probably 8p11-q11. By fluorescence in situ hybridization, Najfeld et al. (1993) narrowed the assignment to chromosome 8p12-p11.
Logan et al. (2002) observed reduced proliferation by peripheral blood lymphocytes (PBLs) in response to interleukin-2 (IL2; 147680) in the presence of HeLa cells. The inhibition was mediated by IDO (indoleamine 2,3-dioxygenase) released by the tumor cells in response to IFNG secretion by the PBL and could be reversed by 1-methyl-tryptophan, a specific IDO inhibitor. Logan et al. (2002) proposed that IDO activity in tumor cells may act to impair antitumor responses.
Munn et al. (2002) described a subset of human IDO-expressing antigen-presenting cells (APCs) that coexpressed CD123 (IL3RA; 308385) and CCR6 (601835) and inhibited T-cell proliferation. Among dendritic cells (DCs), both mature and immature CD123-positive DCs suppressed T-cell activity using IDO, and such cells could be detected in inflamed tonsil tissue. Flow cytometric analysis demonstrated constitutive IDO expression in CD123-positive DCs that was upregulated after IFNG activation. IDO suppressive activity could be blocked by 1-methyl-tryptophan (1MT).
Uyttenhove et al. (2003) demonstrated that most human tumors constitutively express IDO. They also observed that expression of Ido by immunogenic mouse tumor cells prevents their rejection by preimmunized mice. This effect is accompanied by a lack of accumulation of specific T cells at the tumor site and can be partly reverted by systemic treatment of mice with an inhibitor of Ido, in the absence of noticeable toxicity. Uyttenhove et al. (2003) concluded that the efficacy of therapeutic vaccination of cancer patients might be improved by concomitant administration of an IDO inhibitor.
CD4 (186940)-positive/CD25 (147730)-positive regulatory T (Tr) cells exert control over the immune response by interacting with APCs, particularly DCs. Fallarino et al. (2003) showed that Cd4-positive/Cd25-positive mouse Tr cells expressing Ctla4 (123890) conditioned B7 (CD80; 112203)-expressing DCs to express Ido and produce Ifng. DCs conditioned in vitro by Tr cells mediated suppressive effects in vivo that were dependent on effective tryptophan catabolism. The requirement for Ctla4 expression was overcome in Tr cells stimulated with lipopolysaccharide to produce substantial amounts of Ifng and Il10 (124092). Fallarino et al. (2003) concluded that Tr cells prime DCs for tolerance induction through IDO-based immunoregulation.
Using a soluble form of Gitr (TNFRSF18; 603905), Grohmann et al. (2007) found that mouse plasmacytoid DCs (pDCs) possessed Gitr ligand (GITRL, or TNFSF18; 603898) and that reverse signaling through Gitrl resulted in noncanonic Nfkb (see 164011) activation and onset of IDO-dependent immune regulation. Administration of dexamethasone to mice activated IDO through concordant induction of Gitr in Cd4-positive T cells and Gitrl in pDCs and contributed to protection from allergic bronchopulmonary aspergillosis (see 614079). Grohmann et al. (2007) proposed that GITRL-dependent modulation of tryptophan catabolism may represent an important mechanism of action of glucocorticoids, both physiologically and therapeutically.
Thomas et al. (2007) found that NO donors did not affect expression of IDO, but instead reversibly inhibited IDO activity in IFNG (147570)-activated human monocyte-derived macrophages. Similar findings were observed with purified recombinant human IDO. Spectroscopic analysis showed that NO reversibly inhibited IDO activity by binding to its heme moiety rather than modifying amino acids. NO inactivation of IDO was reversible by loss of a Fe(2+)-NO-trp species. Kinetic studies revealed that NO reacted most rapidly with Fe(2+) IDO in the presence of trp. The results demonstrated that the NO-inactivated IDO species was a Fe(2+)-NO-trp heme adduct.
Maghzal et al. (2008) showed that superoxide anion radical was a poor activator of recombinant human IDO or endogenous IDO in various human cells in the absence of methylene blue. Recombinant human cytochrome b5 (CYB5A; 613218) reduced Fe(3+)-IDO to Fe(2+)-IDO and activated IDO in the presence of cytochrome P450 reductase (POR; 124015) and an NADPH-regenerating system. Knockdown of cytochrome b5 significantly decreased IDO activity in HEK293 cells. The results demonstrated that cytochrome b5 activated IDO in human cells without superoxide.
During inflammation, IDO is upregulated in dendritic cells and phagocytes by proinflammatory stimuli, most notably IFNG, and the enzyme then uses superoxide as a 'cofactor' for oxidative cleavage of the indole ring of tryptophan, yielding an intermediate that deformylates to L-kynurenine. Romani et al. (2008) demonstrated that a superoxide-dependent step in tryptophan metabolism along the kynurenine pathway is blocked in chronic granulomatous disease (CGD; 233700) mice deficient in p47 (608512) with lethal pulmonary aspergillosis, leading to unrestrained V-gamma-1+ gamma-delta T-cell reactivity, dominant production of interleukin-17 (IL17; 603149), defective regulatory T-cell activity, and acute inflammatory lung injury. Although beneficial effects are induced by IL17 neutralization or gamma-delta T-cell contraction, complete cure and reversal of the hyperinflammatory phenotype are achieved by replacement therapy with a natural kynurenine distal to the blockade in the pathway. Effective therapy, which includes coadministration of recombinant IFNG, restores production of downstream immunoactive metabolites and enables the emergence of regulatory V-gamma-4+ gamma-delta and Foxp3+ (300292) alpha-beta T cells. Therefore, Romani et al. (2008) concluded that paradoxically, the lack of reactive oxygen species contributes to the hyperinflammatory phenotype associated with NADPH oxidase deficiencies, through a dysfunctional kynurenine pathway of tryptophan catabolism. Yet this condition can be reverted by reactivating the pathway downstream of the superoxide-dependent step.
Wang et al. (2010) demonstrated that infection of mice with malarial parasites or induction of endotoxemia in mice led to endothelial expression of Ido, decreased plasma tryptophan concentration, increased kynurenine concentration, and hypotension. Pharmacologic inhibition of Ido increased blood pressure in systemically inflamed mice but not in mice deficient in Ido or Ifng. Both tryptophan and kynurenine dilated preconstricted porcine coronary arteries; the dilating effect of tryptophan required the presence of active Ido and an intact endothelium, whereas the effect of kynurenine was endothelium-independent. The kynurenine-induced arterial relaxation was mediated by activation of the adenylate (see 103072) and soluble guanylate cyclase (see 139396) pathways. Kynurenine administration decreased blood pressure in a dose-dependent manner in spontaneously hypertensive rats. Wang et al. (2010) concluded that tryptophan metabolism by IDO contributes to the regulation of vascular tone.
Bessede et al. (2014) found that a first exposure of mice to lipopolysaccharide (LPS) activated the ligand-operated transcription factor aryl hydrocarbon receptor (AHR; 600253) and the hepatic enzyme tryptophan 2,3-dioxygenase (TDO2; 191070), which provided an activating ligand to the former, to downregulate early inflammatory gene expression. However, on LPS rechallenge, Ahr engaged in long-term regulation of systemic inflammation only in the presence of Ido1. Ahr complex-associated Src kinase activity promoted Ido1 phosphorylation and signaling ability. The resulting endotoxin-tolerant state was found to protect mice against immunopathology in gram-negative and gram-positive infections, pointing to a role for Ahr in contributing to host fitness.
Spinelli et al. (2019) found that the mouse Ido1 locus was hypermethylated on the paternal allele, showed low methylation on the maternal allele, and was partially methylated in E9.5 placenta. Examination of the chromatin immunoprecipitation-sequencing data revealed that mouse sperm was enriched in the repressive histone mark H3K27me3 and depleted of the activating histone mark H3K4me3 at the Ido1 locus, and that this differential enrichment was linked to imprinted expression of Ido1. Comparison of the DNA methylation patterns of E9.5 mouse placenta showed that altered DNA methylation of the Ido1 gene was related to spontaneous pregnancy loss in a mouse model. The human IDO1 locus also showed methylation patterns consistent with imprinted genes, as it was hypermethylated in sperm, hypomethylated in oocytes, and partially methylated in first-trimester placenta. Analysis with euploid human placentas from first-trimester miscarriages revealed significant differences in IDO1 methylation patterns relative to placentas from uncomplicated pregnancies.
Survival of long-lived plasma cells (LLPCs) requires their interaction with LLPC niche stromal cells for long-term protective immunity by continual production of neutralizing antibodies (Abs). Lightman et al. (2021) found that Ido1 was involved in LLPC biology, as Ido1 -/- mice had diminished bone marrow (BM) PC numbers and durable Ab titers. In vitro analysis showed that active Ido1 was directly induced in DCs by BM PCs through Cd28 (186760)-Cd80 (112203)/Cd86 (601020) interaction. Subsequently, active Ido1 generated kynurenine to activate Ahr in LLPCs and mediate its pro-LLPC survival effects via Ahr-induced upregulation of Cd28 expression. In vivo analysis with mice showed that DCs were necessary to maintain BM LLPCs and long-lived Ab responses, as DCs were the primary producers of Ido1 in maintaining LLPC populations and persistent Ab titers for long-term protective immunity.
As pointed out more than 40 years ago by Peter Medawar, survival of the genetically disparate (allogeneic) mammalian conceptus contradicts the laws of tissue transplantation (Medawar, 1953). It appears that anatomic separation of mother and fetus and antigenic immaturity of the fetus cannot explain fetal allograft survival. Attention therefore focused on a third mechanism, namely immunologic 'inertness' (tolerance) of the mother. Certain macrophages, induced to express IDO in response to interferon-gamma and other signals from activating T cells, inhibit T-cell proliferation in vitro by rapidly consuming tryptophan. Because IDO is also expressed by human syncytiotrophoblast cells and systemic tryptophan concentration falls during normal pregnancy, Munn et al. (1998) formulated the hypothesis that IDO expression at the maternal-fetal interface is necessary to prevent immunologic rejection of the fetal allografts. To test this hypothesis, they exposed pregnant mice (carrying syngeneic or allogeneic fetuses) to 1-methyl-tryptophan, the pharmacologic agent that inhibits IDO enzyme activity. They found that rapid T cell-induced rejection of all allogeneic concepti occurred when pregnant mice were treated with the inhibitor. Thus, by catabolizing tryptophan, the mammalian conceptus suppresses T-cell activity and defends itself against rejection.
Mellor et al. (2002) showed that T cells cocultured with cells expressing murine Ido did not proliferate, even in the presence of allogeneic cells, but did express activation markers. Adoptive transfer experiments determined that allogeneic T-cell numbers were reduced in Ido transgenic mice.
Grohmann et al. (2002) noted that a fusion protein of Ctla4 with immunoglobulin (Ctla4-Ig) blocked allograft and xenograft rejection in models of cardiac, liver, and pancreatic islet transplantation, but that B7 expression was required in cardiac donor cells. They hypothesized that, after binding, both Ctla4 and B7 are activated, changing the functional state of both the T cell and the APC. Grohmann et al. (2002) found that in the presence of the IDO inhibitor, 1-methyltryptophan (1MT), Ctla4-Ig was unable to promote engraftment of islet cells in mice. In vitro, Ctla4-Ig treatment resulted in an increased rate of tryptophan degradation to kynurenine to an extent similar to that induced by Ifng and required the presence of B7 molecules on DCs. Indeed, DCs expressing B7 produced enhanced levels of Ifng, but not tumor necrosis factor (TNF; 191160), in response to Ctla4 ligation. Expression of both Ifng and Stat1 (600555) was required for kynurenine production and Ctla4 suppression of the rejection response, suggesting that Ifng can act on tolerogenic DCs in an autocrine or paracrine manner.
Using a mouse knockout model, Muller et al. (2005) demonstrated that Bin1 (601248) loss elevated the Stat1- and Nfkb-dependent expression of Indo, driving escape of oncogenically transformed cells from T cell-dependent antitumor immunity. In a mouse breast cancer model, coadministration of small-molecule inhibitors of Indo and cytotoxic agents elicited regression of established tumors refractory to single-agent therapy. Muller et al. (2005) suggested that BIN1 loss promotes immune escape in cancer by deregulating INDO and that INDO inhibitors may improve responses to cancer chemotherapy.
Too et al. (2016) generated mice lacking Tdo2, Ido1, or Ido2 (612129) and assessed their behavior and cognitive function during 2 periods separated by 1 month. Ido1 -/- mice displayed reductions of early diurnal exploration in both periods. In contrast, Ido2 -/- mice showed early diurnal hyperactivity in both periods. Tdo2 -/- mice displayed increased diurnal and nocturnal activity, but only in the second period. Ido2 -/- mice appeared to have enhanced reference memory in a complex patrolling task, and Tdo2 -/- mice exhibited enhanced performance in complex patrolling and discrimination reversal tasks. Neurochemical measurements revealed attenuated serotonin levels in Ido1 -/- mice, augmented tryptophan and serotonin levels in Tdo2 -/- mice, and no neurochemical alterations in Ido2 -/- mice. Too et al. (2016) concluded that Ido1, Ido2, and Tdo2 deficiencies differentially affect exploratory behavior and learning performance, as well as metabolism of kynurenine, serotonin, and dopamine, in mice.
Bessede, A., Gargaro, M., Pallotta, M. T., Matino, D., Servillo, G., Brunacci, C., Bicciato, S., Mazza, E. M. C., Macchiarulo, A., Vacca, C., Iannitti, R., Tissi, L., and 26 others. Aryl hydrocarbon receptor control of a disease tolerance defence pathway. Nature 511: 184-190, 2014. [PubMed: 24930766] [Full Text: https://doi.org/10.1038/nature13323]
Burkin, D. J., Kimbro, K. S., Barr, B. L., Jones, C., Taylor, M. W., Gupta, S. L. Localization of the human indoleamine 2,3-dioxygenase (IDO) gene to the pericentromeric region of human chromosome 8. Genomics 17: 262-263, 1993. [PubMed: 8406467] [Full Text: https://doi.org/10.1006/geno.1993.1319]
Dai, W., Gupta, S. L. Molecular cloning, sequencing and expression of human interferon-gamma-inducible indoleamine 2,3-dioxygenase cDNA. Biochem. Biophys. Res. Commun. 168: 1-8, 1990. [PubMed: 2109605] [Full Text: https://doi.org/10.1016/0006-291x(90)91666-g]
Fallarino, F., Grohmann, U., Hwang, K. W., Orabona, C., Vacca, C., Bianchi, R., Belladonna, M. L., Fioretti, M. C., Alegre, M.-L., Puccetti, P. Modulation of tryptophan catabolism by regulatory T cells. Nature Immun. 4: 1206-1212, 2003. [PubMed: 14578884] [Full Text: https://doi.org/10.1038/ni1003]
Grohmann, U., Orabona, C., Fallarino, F., Vacca, C., Calcinaro, F., Falorni, A., Candeloro, P., Belladonna, M. L., Bianchi, R., Fioretti, M. C., Puccetti, P. CTLA-4-Ig regulates tryptophan catabolism in vivo. Nature Immun. 3: 1097-1101, 2002. [PubMed: 12368911] [Full Text: https://doi.org/10.1038/ni846]
Grohmann, U., Volpi, C., Fallarino, F., Bozza, S., Bianchi, R., Vacca, C., Orabona, C., Belladonna, M. L., Ayroldi, E., Nocentini, G., Boon, L., Bistoni, F., Fioretti, M. C., Romani, L., Riccardi, C., Puccetti, P. Reverse signaling through GITR ligand enables dexamethasone to activate IDO in allergy. Nature Med. 13: 579-586, 2007. [PubMed: 17417651] [Full Text: https://doi.org/10.1038/nm1563]
Kadoya, A., Tone, S., Maeda, H., Minatogawa, Y., Kido, R. Gene structure of human indoleamine 2,3-dioxygenase. Biochem. Biophys. Res. Commun. 189: 530-536, 1992. [PubMed: 1449503] [Full Text: https://doi.org/10.1016/0006-291x(92)91590-m]
Lightman, S. M., Peresie, J. L., Carlson, L. M., Holling, G. A., Honikel, M. M., Chavel, C. A., Nemeth, M. J., Olejniczak, S. H., Lee, K. P. Indoleamine 2,3-dioxygenase 1 is essential for sustaining durable antibody responses. Immunity 54: 2772-2783, 2021. [PubMed: 34788602] [Full Text: https://doi.org/10.1016/j.immuni.2021.10.005]
Logan, G. J., Smyth, C. M. F., Earl, J. W., Zaikina, I., Rowe, P. B., Smythe, J. A., Alexander, I. E. HeLa cells cocultured with peripheral blood lymphocytes acquire an immuno-inhibitory phenotype through up-regulation of indoleamine 2,3-dioxygenase activity. Immunology 105: 478-487, 2002. [PubMed: 11985668] [Full Text: https://doi.org/10.1046/j.1365-2567.2002.01390.x]
Maghzal, G. J., Thomas, S. R., Hunt, N. H., Stocker, R. Cytochrome b5, not superoxide anion radical, is a major reductant of indoleamine 2,3-dioxygenase in human cells. J. Biol. Chem. 283: 12014-12025, 2008. [PubMed: 18299324] [Full Text: https://doi.org/10.1074/jbc.M710266200]
Medawar, P. B. Some immunological and endocrinological problems raised by the evolution of viviparity in vertebrates. Symp. Soc. Exp. Biol. 7: 320-338, 1953.
Mellor, A. L., Keskin, D. B., Johnson, T., Chandler, P., Munn, D. H. Cells expressing indoleamine 2,3-dioxygenase inhibit T cell responses. J. Immun. 168: 3771-3776, 2002. [PubMed: 11937528] [Full Text: https://doi.org/10.4049/jimmunol.168.8.3771]
Muller, A. J., DuHadaway, J. B., Donover, P. S., Sutanto-Ward, E., Prendergast, G. C. Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy. Nature Med. 11: 312-319, 2005. [PubMed: 15711557] [Full Text: https://doi.org/10.1038/nm1196]
Munn, D. H., Sharma, M. D., Lee, J. R., Jhaver, K. C., Johnson, T. S., Keskin, D. B., Marshall, B., Chandler, P., Antonia, S. J., Burgess, R., Slingluff, C. L., Jr., Mellor, A. L. Potential regulatory function of human dendritic cells expressing indoleamine 2,3-dioxygenase. Science 297: 1867-1870, 2002. [PubMed: 12228717] [Full Text: https://doi.org/10.1126/science.1073514]
Munn, D. H., Zhou, M., Attwood, J. T., Bondarev, I., Conway, S. J., Marshall, B., Brown, C., Mellor, A. L. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 281: 1191-1193, 1998. [PubMed: 9712583] [Full Text: https://doi.org/10.1126/science.281.5380.1191]
Najfeld, V., Menninger, J., Muhleman, D., Comings, D. E., Gupta, S. L. Localization of indoleamine 2,3-dioxygenase gene (INDO) to chromosome 8p12-p11 by fluorescent in situ hybridization. Cytogenet. Cell Genet. 64: 231-232, 1993. [PubMed: 8404046] [Full Text: https://doi.org/10.1159/000133584]
Romani, L., Fallarino, F., De Luca, A., Montagnoli, C., D'Angelo, C., Zelante, T., Vacca, C., Bistoni, F., Fioretti, M. C., Grohmann, U., Segal, B. H., Puccetti, P. Defective tryptophan catabolism underlies inflammation in mouse chronic granulomatous disease. Nature 451: 211-215, 2008. [PubMed: 18185592] [Full Text: https://doi.org/10.1038/nature06471]
Spinelli, P., Latchney, S. E., Reed, J. M., Fields, A., Baier, B. S., Lu, X., McCall, M. N., Murphy, S. P., Mak, W., Susiarjo, M. Identification of the novel Ido1 imprinted locus and its potential epigenetic role in pregnancy loss. Hum. Molec. Genet. 28: 662-674, 2019. [PubMed: 30403776] [Full Text: https://doi.org/10.1093/hmg/ddy383]
Thomas, S. R., Terentis, A. C., Cai, H., Takikawa, O., Levina, A., Lay, P. A., Freewan, M., Stocker, R. Post-translational regulation of human indoleamine 2,3-dioxygenase activity by nitric oxide. J. Biol. Chem. 282: 23778-23787, 2007. [PubMed: 17535808] [Full Text: https://doi.org/10.1074/jbc.M700669200]
Too, L. K., Li, K. M., Suarna, C., Maghzal, G. J., Stocker, R., McGregor, I. S., Hunt, N. H. Deletion of TDO2, IDO-1 and IDO-2 differentially affects mouse behavior and cognitive function. Behav. Brain Res. 312: 102-117, 2016. [PubMed: 27316339] [Full Text: https://doi.org/10.1016/j.bbr.2016.06.018]
Uyttenhove, C., Pilotte, L., Theate, I., Stroobant, V., Colau, D., Parmentier, N., Boon, T., Van den Eynde, B. J. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nature Med. 9: 1269-1274, 2003. [PubMed: 14502282] [Full Text: https://doi.org/10.1038/nm934]
Wang, Y., Liu, H., McKenzie, G., Witting, P. K., Stasch, J.-P., Hahn, M., Changsirivathanathamrong, D., Wu, B. J., Ball, H. J., Thomas, S. R., Kapoor, V., Celermajer, D. S., Mellor, A. L., Keaney, J. F., Jr., Hunt, N. H., Stocker, R. Kynurenine is an endothelium-derived relaxing factor produced during inflammation. Nature Med. 16: 279-285, 2010. Note: Erratum: Nature Med. 16: 607 only, 2010. [PubMed: 20190767] [Full Text: https://doi.org/10.1038/nm.2092]