Indoleamine-pyrrole 2,3-dioxygenase (IDO or INDO EC 1.13.11.52) is an enzyme secreted by activated macrophages and other immunoregulatory cells. This enzyme catalyzes the degradation of L-tryptophan to N-formylkynurenine.
CHEMICAL STRUCTURE AND IMAGES
When relevant for the function
- Primary structure
- Secondary structure
- Tertiary structure
- Quaternary structure
AA %
Similar proteins
ID PAN2_HUMAN 1202 AA.
ID TSSK3_HUMAN 268 AA.
ID TTC13_HUMAN 860 AA.
ID PRKDC_HUMAN 4128 AA.
ID RYR2_HUMAN 4965 AA.
ID ULK3_HUMAN 214 AA.
ID RYR3_HUMAN 4870 AA.
ID PK3CB_HUMAN 1070 AA.
ID UBR3_HUMAN 1888 AA.
ID KS6A6_HUMAN 745 AA.
ID PI4KA_HUMAN 2044 AA.
PI3K and IDO
Immune escape as a fundamental trait of cancer: focus on IDO. 2008
SYNTHESIS AND TURNOVER
mRNA synthesis
Tissue mRNA
CELLULAR FUNCTIONS
cellular localization,
biological function
- Enzymes
- Cell signaling and Ligand transport
- Structural proteins
REGULATION
Expression modulation
Iron
Iron modulates interferon-gamma effects in the human myelomonocytic cell line THP-1. 1992
IFN-gamma
It is induced by IFN-gamma.
IDO induction has been correlated with induction of GTP-cyclohydrolase, the key enzyme in pteridine biosynthesis. A direct role for IDO in pteridine synthesis has not been shown, and this parallel induction may reflect coordinate regulation of genes induced by IFN-gamma
Relationship between interferon-gamma, indoleamine 2,3-dioxygenase, and tryptophan catabolism. 1991
Targeting the mechanisms of tumoral immune tolerance with small-molecule inhibitors 2006
IDO/PI3K (conflicting??)
- Indoleamine 2,3-dioxygenase (IDO), a tryptophan catabolizing enzyme, has been implicated in the pathogenesis of various neurological disorders. IDO expression is induced by IFN-gamma and leads to neurotoxicity by generating quinolinic acid. Additionally, it inhibits the immune response through both tryptophan depletion and generating other tryptophan catabolites. IL-4 and IL-13 have been shown to control IDO expression by antagonizing the effects of IFN-gamma in different cell types. Here, we investigated the effects of these cytokines on IDO expression in microglia. Interestingly, we observed that both IL-4 and IL-13 greatly enhanced IFN-gamma-induced IDO expression. However, tryptophanyl-tRNA synthetase (WRS), which is coinduced with IDO by IFN-gamma, is downregulated by IL-4 and IL-13. The effect of IL-4 and IL-13 was independent of STAT-6. Modulation of IDO but not WRS was eliminated by inhibition of protein phosphatase 2A (PP2A) activity. The phosphatidylinositol 3-kinase (PI3K) pathway further differentiated the regulation of these two enzymes, as inhibiting the PI3K pathway eliminated IFN-gamma induction of IDO, whereas such inhibition greatly enhanced WRS expression. These findings show discordance between modulations of expression of two distinct enzymes utilizing tryptophan as a common substrate, and raise the possibility of their involvement in regulating immune responses in various neurological disorders.
IFN-gamma-induced IDO and WRS expression in microglia is differentially regulated by IL-4. 2007
- CD8 and CD8 dendritic cells (DCs) are distinct subsets of mouse splenic accessory cells with opposite but flexible programs of Ag presentation, leading to immunogenic and tolerogenic responses, respectively. In this study, we show that the default tolerogenic function of CD8 DCs relies on autocrine TGF-beta, which sustains the activation of IDO in response to environmental stimuli. CD8 DCs do not produce TGF-beta, yet externally added TGF-beta induces IDO and turns those cells from immunogenic into tolerogenic cells. The acquisition of a suppressive phenotype (no IDO) by CD8 DCs correlates with activation of the PI3K/Akt and noncanonical NF-kappaB pathways. These data are the first to link TGF-beta signaling with IDO in controlling spontaneous tolerogenesis by DCs.
Cutting edge: Autocrine TGF-beta sustains default tolerogenesis by IDO-competent dendritic cells. 2008
- This indoleamine may regulate growth and differentiation of pancreatic islets by activating IGF-I and insulin receptor signaling pathways.
Activation of insulin and IGF-1 signaling pathways by melatonin through MT1 receptor in isolated rat pancreatic islets. 2008
Virus effect
he innate immunity to viral infections induces a potent antiviral response mediated by interferons (IFN). Although IFN-gamma is detected during the acute stages of illness in the upper respiratory tract secretions and in the serum of influenza A virus-infected individuals, control of influenza A virus is not dependent upon IFN-gamma as evidenced by studies using anti-IFN-gamma Ab and IFN-gamma(-/-) mice. Thus, we hypothesized that IFN-gamma is not critical in host survival because influenza A virus has mechanisms to evade the antiviral activity of IFN-gamma. To test this, A549 cells, an epithelial cell line derived from lung adenocarcinoma, were infected with influenza virus strain A/Aichi/2/68 (H3N2) (Aichi) and/or stimulated with IFN-gamma to detect IFN-gamma-stimulated MHC class II expression. Influenza A virus infection inhibited IFN-gamma-induced up-regulation of HLA-DRalpha mRNA and the IFN-gamma induction of class II transactivator (*CIITA* inhibited by Statins), an obligate mediator of MHC class II expression. Nuclear translocation of Stat1alpha upon IFN-gamma stimulation was significantly inhibited in influenza A virus-infected cells and this was associated with a decrease in Tyr701 and Ser727 phosphorylation of Stat1alpha. Thus, influenza A virus subverts antiviral host defense mediated by IFN-gamma through effects on the intracellular signaling pathways.
Influenza A virus abrogates IFN-gamma response in respiratory epithelial cells by disruption of the Jak/Stat pathway. 2008
Indoleamine-2, 3-dioxygenase and other interferon-gamma-mediated pathways in patients with human immunodeficiency virus infection. 2007
Drugs modulation
Curcumin suppresses the induction of indoleamine 2,3-dioxygenase by blocking the Janus-activated kinase-protein kinase Cdelta-STAT1 signaling pathway in interferon-gamma-stimulated murine dendritic cells. 2009
Resveratrol suppresses interferon-gamma-induced biochemical pathways in human peripheral blood mononuclear cells in vitro. 2005
Inhibition by Brassinin
- The importance of IDO dysregulation manifest as autoimmune pellagric dementia is genetically illustrated for Nasu-Hakola Disease (or PLOSL), which is caused by a mutation in the IDO antagonizing genes TYROBP/DAP12 or TREM2. Loss of function leads to psychotic symptoms rapidly progressing to presenile dementia likely due to unchecked increases in microglial IDO expression, which depletes neurons of tryptophan causing neurodegeneration.
- Chronic elevation of TNFalpha leading to necrotic events by NAD depletion in autoimmune disease likely occurs via combination of persistent IDO activation and iNOS-peroxynitrate activation of PARP1 both of which deplete NAD
- among the NAD precursors, nicotinic acid specifically activates the g-protein coupled receptor (GPCR) GPR109a to produce the IDO-inducing tolerogenic prostaglandins PGE and PGD. Next, PGD is converted to the anti-inflammatory prostaglandin, 15d-PGJ. These prostaglandins exert potent anti-inflammatory activities through endogenous signaling mechanisms involving the GPCRs EP2, EP4, and DP1 along with PPARgamma respectively.
- direct targeting of the non-redox NAD-dependent proteins using resveratrol to activate SIRT1 or PJ34 in order to inhibit PARP1
Pharmacological targeting of IDO-mediated tolerance for treating autoimmune disease. 2007
Effects of Tryptophan deficiency
IDO is the first and rate limiting enzyme of Tryptophan catabolism through Kynurenine pathway, thus causing depletion of tryptophan which can cause halted growth of:
- T cells.
- many tumor cells
- intracellular pathogens
- Toxoplasma
- Chlamydia. (References)
Kynurenine as a sign of Tryptophan deficiency
Kynurenin is expected to inhibit synthesis of proteins rich of Trp (> 2.50 %)
and to activate synthesis of proteins poor of Trp (< 0.80 %)
Effect of amino acid metabolites on lysosomal protein degradation. A regulatory role for kynurenine? 1984
Grinde B.
Eur J Biochem. 1984 Dec 17;145(3):623-7.
Possible derivatives of the amino acids tryptophan, tyrosine and histidine were examined as to their effect on protein metabolism in isolated rat hepatocytes. One of the substances tested, kynurenine (a main product of the catabolism of tryptophan), might be a physiological regulator of the lysosomal degradation of endogenous protein, because of the following. (a) Kynurenine decreased the lysosomal (i.e. methylamine-sensitive) pathway of degradation to a much greater extent than its parent amino acid, without interfering with the non-lysosomal pathway. (b) Kynurenine did not appreciably reduce the (lysosomal) degradation of the endocytosed protein asialo-fetuin, or the rate of protein synthesis, indicating a specificity of action. © Electron micrographs revealed a reduction in secondary lysosomes due to kynurenine. FullText
Papers Kynurenine Immune Tolerance
Trp and Arg depletion
Creating immune privilege: active local suppression that benefits friends, but protects foes 2008
DIAGNOSTIC USE
Histone deacetylase inhibition modulates indoleamine 2,3-dioxygenase–dependent DC functions and regulates experimental graft-versus-host disease in mice 2008
J Immunol. 2008 Oct 15;181(8):5396-404.
The indoleamine 2,3-dioxygenase pathway is essential for human plasmacytoid dendritic cell-induced adaptive T regulatory cell generation.
Chen W, Liang X, Peterson AJ, Munn DH, Blazar BR.
Human plasmacytoid dendritic cells (PDCs) can drive naive, allogeneic CD4CD25 T cells to differentiate into CD4CD25Foxp3 regulatory T cells (Tregs). However, the intracellular mechanism or mechanisms underlying PDC-induced Treg generation are unknown. In this study, we show that human PDCs express high levels of IDO, an intracellular enzyme that catabolizes tryptophan degradation. Triggering of TLR 9 with CpG oligodeoxynucleotides activates PDCs to up-regulate surface expression of B7 ligands and HLA-DR Ag, but also significantly increases the expression of IDO and results in the generation of inducible Tregs from CD4CD25 T cells with potent suppressor cell function. Blocking IDO activity with the pharmacologic inhibitor 1-methyl-D-tryptophan significantly abrogates PDC-driven inducible Treg generation and suppressor cell function. Adding kynurenine, the immediate downstream metabolite of tryptophan, bypasses the 1-methyl-D-tryptophan effect and restores PDC-driven Treg generation. Our results demonstrate that the IDO pathway is essential for PDC-driven Treg generation from CD4CD25 T cells and implicate the generation of kynurenine pathway metabolites as the critical mediator of this process.
J Leukoc Biol. 2008 Apr;83(4):894-901. Epub 2008 Jan 2.
Chorionic gonadotropin induces dendritic cells to express a tolerogenic phenotype.
Wan H, Versnel MA, Leijten LM, van Helden-Meeuwsen CG, Fekkes D, Leenen PJ, Khan NA, Benner R, Kiekens RC.
Department of Immunology, Erasmus MC, Dr. Molewaterplein 50, NL-3015 GE Rotterdam, The Netherlands. h.wan@erasmusmc.nl.
The pregnancy hormone human chorionic gonadotropin (hCG) has been suggested to play an immunoregulatory role in addition to its endocrine function, thus contributing to the prevention of fetal rejection. We hypothesized that hCG is involved in the maternal-fetal immune tolerance by the regulation of dendritic cell (DC) function. Therefore, we studied the effect of hCG on DC maturation. Upon hCG treatment in combination with LPS, mouse bone marrow-derived DC (BMDC) increased the ratio of IL-10:IL-12p70, down-regulated TNF-alpha, and decreased antigen-specific T cell proliferation. Addition of hCG together with LPS and IFN-gamma blocked MHC class II up-regulation, increased IL-10 production, and decreased the antigen-specific T cell proliferation by DC. Splenic DC showed similar results. Upon hCG treatment, IDO mRNA expression and its metabolite kynurenine were increased by LPS- and IFN-gamma-stimulated DC, suggesting its involvement in the decreased T cell proliferation. To study the effect of hCG on DC differentiation from precursors, BMDC were generated in the continuous presence of hCG. Under this condition, hCG decreased cytokine production and the induction of T cell proliferation. These data are suggestive for a contribution of hCG to the maternal-fetal tolerance during pregnancy by modifying DC toward a tolerogenic phenotype.
Kynurenic acid triggers firm arrest of leukocytes to vascular endothelium under flow conditions. 2009
Papers Kynurenine urine determination
J Neurol Sci. 2009 Aug 15;283(1-2):21-7. Epub 2009 Mar 5.
The role of kynurenines in disorders of the central nervous system: possibilities for neuroprotection.
The metabolism of tryptophan mostly proceeds through the kynurenine pathway. The biochemical reaction includes both an agonist (quinolinic acid) at the N-methyl-d-aspartate receptor and an antagonist (kynurenic acid). Besides the N-methyl-d-aspartate antagonism, an important feature of kynurenic acid is the blockade of the alpha7-nicotinic acetylcholine receptor and its influence on the alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptor. Kynurenic acid has proven to be neuroprotective in several experimental settings. On the other hand, quinolinic acid is a potent neurotoxin with an additional and marked free radical-producing property. In consequence of these various receptor activities, the possible roles of these substances in various neurological disorders have been proposed. Moreover, the possibility of influencing the kynurenine pathway to reduce quinolinic acid and increase the level of kynurenic acid in the brain offers a new target for drug action designed to change the balance, decreasing excitotoxins and enhancing neuroprotectants. This review surveys both the early and the current research in this field, focusing on the possible therapeutic effects of kynurenines.
