Indoleamine-pyrrole 2,3-dioxygenase (IDO or INDO) is involved in tryptophan metabolism

July 18, 2023
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Indoleamine-pyrrole 2,3-dioxygenase (IDO or INDO EC 1.13.11.52) is a heme-containing enzyme physiologically expressed in a number of tissues and cells, such as the small intestine, lungs, female genital tract or placenta.

In humans is encoded by the IDO1 gene.

IDO is involved in tryptophan metabolism. It is one of three enzymes that catalyze the first and rate-limiting step in the kynurenine pathway, the O2-dependent oxidation of L-tryptophan to N-formylkynurenine, the others being indolamine-2,3-dioxygenase 2 (IDO2) and tryptophan 2,3-dioxygenase (TDO).

N′-Formylkynurenine is an intermediate in the catabolism of tryptophan. It is a formylated derivative of kynurenine. The formation of N′-formylkynurenine is catalyzed by heme dioxygenases.

N′-formylkynurenine pathways:

IDO is an important part of the immune system and plays a part in natural defense against various pathogens. It is produced by the cells in response to inflammation and has an immunosuppressive function because of its ability to limit T-cell function and engage mechanisms of immune tolerance.

Emerging evidence suggests that IDO becomes activated during tumor development, helping malignant cells escape eradication by the immune system. Expression of IDO has been described in a number of types of cancer, such as acute myeloid leukemia, ovarian cancer or colorectal cancer. IDO is part of the malignant transformation process and plays a key role in suppressing the anti-tumor immune response in the body, so inhibiting it could increase the effect of chemotherapy as well as other immunotherapeutic protocols.

Physiological function

Indoleamine 2,3-dioxygenase is the first and rate-limiting enzyme of tryptophan catabolism through the kynurenine pathway.

IDO is an important molecule in the mechanisms of tolerance and its physiological functions include the suppression of potentially dangerous inflammatory processes in the body.

IDO also plays a role in natural defense against microorganisms. Expression of IDO is induced by interferon-gamma, which explains why the expression increases during inflammatory diseases or even during tumorigenesis.

Since tryptophan is essential for the survival of pathogens, the activity of enzyme IDO destroys them. Microorganisms susceptible to tryptophan deficiency include bacteria of genus Streptococcus or viruses such as herpes simplex or measles.

One of the organs with high IDO expression is the placenta. In the 1990s, the immunosuppressive function of this enzyme was first described in mice due to the study of placental tryptophan metabolism. Thus, mammalian placenta, due to intensive tryptophan catabolism has the ability to suppress T cell activity, thereby contributing to its position of immunologically privileged tissue.

Clinical significance

IDO is an immune checkpoint molecule in the sense that it is an immunomodulatory enzyme produced by alternatively activated macrophages and other immunoregulatory cells.

IDO is known to suppress T and NK cells (aka natural killer cells or large granular lymphocytes (LGL), a type of cytotoxic lymphocyte critical to the innate immune system that belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represent 5–20% of all circulating lymphocytes in humans.), generate Tregs and myeloid-derived suppressor cells, and also supports angiogenesis.

Note: The regulatory T cells (Tregs or Treg cells), formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Treg cells are immunosuppressive and generally suppress or downregulate induction and proliferation of effector T cells. Treg cells express the biomarkers CD4, FOXP3, and CD25 and are thought to be derived from the same lineage as naïve CD4+ cells. Because effector T cells also express CD4 and CD25, Treg cells are very difficult to effectively discern from effector CD4+, making them difficult to study. Research has found that the cytokine transforming growth factor beta (TGF-β) is essential for Treg cells to differentiate from naïve CD4+ cells and is important in maintaining Treg cell homeostasis. The immune system must be able to discriminate between self and non-self. When self/non-self discrimination fails, the immune system destroys cells and tissues of the body and as a result causes autoimmune diseases. Regulatory T cells actively suppress activation of the immune system and prevent pathological self-reactivity, i.e. autoimmune disease. The critical role regulatory T cells play within the immune system is evidenced by the severe autoimmune syndrome that results from a genetic deficiency in regulatory T cells (IPEX syndrome –  Immune dysregulation, Polyendocrinopathy, Enteropathy X-linked (IPEX) syndrome).

Myeloid-derived suppressor cells (MDSC) are a heterogeneous group of immune cells from the myeloid lineage (a family of cells that originate from bone marrow stem cells). MDSCs expand under pathologic conditions such as chronic infection and cancer, as a result of altered haematopoiesis. MDSCs differ from other myeloid cell types in that they have immunosuppressive activities, as opposed to immune-stimulatory properties. Similar to other myeloid cells, MDSCs interact with immune cell types such as T cells, dendritic cells, macrophages and natural killer cells to regulate their functions.  MDSCs are formed from bone marrow precursors when myelopoietic processes are interrupted, caused by several illnesses. Cancer patients’ growing tumors produce cytokines and other substances that affect MDSC development. Tumor cell lines overexpress colony-stimulating factors (G-CSF and GM-CSF) and IL6, which promote development of MDSCs that have immune suppressive function in vivo. Other cytokines, including IL10, IL1, VEGF, and PGE2 have been associated with the formation and regulation of MDSCs. GM-CSF promotes synthesis of MDSCs from bone marrow, and the transcription factor c/EBP regulates development of MDSCs in bone marrow and in tumors. STAT3 also promotes development of MDSCs, whereas IRF8 could counteract MDSC-inducing signals. MDSCs migrate as immature cells from the bone marrow to peripheral tissues (or tumors), where they differentiate into mature macrophages, dendritic cells, and neutrophils without suppressive phenotypes under homeostatic conditions, but become polarized when exposed to pro-inflammatory compounds, chemokines, and cytokines. In the tumor microenvironment, they suppress the anti-tumor immune response. The presence of MDSCs has been associated with progression of colon cancer, tumor angiogenesis, and metastases. In addition to producing NO and ROS, MDSCs secrete immune-regulatory cytokines such as TNF, TGFB, and IL10. There are subpopulations of MDSC that have some common suppressive characteristics but also have their own unique features; different subpopulations can be found in different areas of the same tissue or tumor. Tumor-infiltrating MDSCs develop in response to environmental factors, upregulating CD38 (which removes NAD from the environment and is necessary for mitochondrial biosynthesis), PDL-1 (an immune checkpoint protein) and LOX1 (promotes fatty acid consumption and fatty acid oxidation). Tumor-infiltrating MDSCs also secrete exosomes that can inhibit the anti-tumor immune response. MDSCs are immune suppressive and play a role in tumor maintenance and progression. MDSCs also obstruct therapies that seek to treat cancer through both immunotherapy and other non-immune means. MDSC activity was originally described as suppressors of T cells, in particular of CD8+ T-cell responses. The spectrum of action of MDSC activity also encompasses NK cells, dendritic cells and macrophages. Suppressor activity of MDSC is determined by their ability to inhibit the effector function of lymphocytes. Inhibition can be caused by different mechanisms. It is primarily attributed to the effects of the metabolism of L-arginine. Another important factor influencing the activity of MDSC is oppressive ROS. MDSCs can also play a positive regulatory role. It is stated that MMR vaccine stimulates MDSC populations in people taking the vaccine, inhibiting septic inflammation and mortality that is broadly applicable not only to measles, mumps, and rubella, but extends to covid-19 induced cytokine inflammation.[citation needed] This vaccination inducement appears to be neither permanent nor chronic.[clarification needed] Despite MDSC’s being immunosuppressive in certain instances, the MMR vaccine itself is immunostimulatory. The term myeloid-derived suppressor cell originated in a 2007 journal article published in Cancer Research by Gabrilovich et al. Publications in 2008 established that there are two subpopulations of MDSC: mononuclear MDSC (M-MDSC) and polymorphonuclear or granulocytic MDSC (PMN-MDSC). M-MDSC are similar to monocytes found in blood, while PMN-MDSC are physically akin to neutrophils.

These mechanisms are crucial in the process of carcinogenesis. IDO allows tumor cells to escape the immune system by two main mechanisms. The first mechanism is based on tryptophan depletion from the tumor microenvironment.

The second mechanism is based on the production of catabolic products called kynurenins, that are cytotoxic for T lymphocytes and NK cells.

Overexpression of human IDO (hIDO) is described in a variety of human tumor cell lineages and is often associated with poor prognosis.

  • Okamoto, Aikou; Nikaido, Takashi; Ochiai, Kazunori; Takakura, Satoshi; Takao, Miho; Saito, Misato; Aoki, Yuko; Ishii, Nobuya; Yanaihara, Nozomu; Yamada, Kyosuke; Takikawa, Osamu (November 2007). “Ido serves as a marker of poor prognosis in gene expression profiles of serous ovarian cancer cells”. International Congress Series. 1304: 262–273. doi:10.1016/j.ics.2007.07.053. ISSN 0531-5131.
  • Inaba, Tomoko; Ino, Kazuhiko; Kajiyama, Hiroaki; Shibata, Kiyosumi; Yamamoto, Eiko; Kondo, Shinji; Umezu, Tomokazu; Nawa, Akihiro; Takikawa, Osamu; Kikkawa, Fumitaka (June 2010). “Indoleamine 2,3-dioxygenase expression predicts impaired survival of invasive cervical cancer patients treated with radical hysterectomy”. Gynecologic Oncology. 117 (3): 423–428. doi:10.1016/j.ygyno.2010.02.028. ISSN 0090-8258. PMID 20350764.

Tumors with increased production of IDO include prostate, ovarian, lung or pancreatic cancer or acute myeloid leukemia.

  • Uyttenhove, Catherine; Pilotte, Luc; Théate, Ivan; Stroobant, Vincent; Colau, Didier; Parmentier, Nicolas; Boon, Thierry; Van den Eynde, Benoît J (2003-09-21). “Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase”. Nature Medicine. 9 (10): 1269–1274. doi:10.1038/nm934. ISSN 1078-8956. PMID 14502282. S2CID 10618102.
  • Jiang, Tianze; Sun, Yingying; Yin, Zhichao; Feng, Sen; Sun, Liping; Li, Zhiyu (February 2015). “Research progress of indoleamine 2,3-dioxygenase inhibitors”. Future Medicinal Chemistry. 7 (2): 185–201. doi:10.4155/fmc.14.151. ISSN 1756-8919. PMID 25686005.

Expression of IDO is under physiological conditions regulated by the Bin1 gene, which can be damaged by tumor transformation.

  • Muller, Alexander J; DuHadaway, James B; Donover, P Scott; Sutanto-Ward, Erika; Prendergast, George C (2005-02-13). “Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy”. Nature Medicine. 11 (3): 312–319. doi:10.1038/nm1196. ISSN 1078-8956. PMID 15711557. S2CID 12338548.

Emerging clinical studies suggest that combination of IDO inhibitors with classical chemotherapy and radiotherapy could restore immune control and provide a therapeutic response to generally resistant tumors. Enzyme IDO used by tumors to escape immune surveillance is currently in focus of research and drug discovery efforts, as well as efforts to understand if it could be used as a biomarker for prognosis.

Song X, Si Q, Qi R, Liu W, Li M, Guo M, Wei L, Yao Z. Indoleamine 2,3-Dioxygenase 1: A Promising Therapeutic Target in Malignant Tumor. Front Immunol. 2021 Dec 23;12:800630. doi: 10.3389/fimmu.2021.800630. PMID: 35003126; PMCID: PMC8733291.

Inhibitors

COX-2 inhibitors down-regulate indoleamine 2,3-dioxygenase, leading to a reduction in kynurenine levels as well as reducing proinflammatory cytokine activity.[citation needed]

1-Methyltryptophan is a racemic compound that weakly inhibits indoleamine dioxygenase, but is also a very slow substrate. The specific racemer 1-methyl-d-tryptophan (known as indoximod) is in clinical trials for various cancers.

Epacadostat (INCB24360), navoximod (GDC-0919), and linrodostat (BMS-986205) are potent inhibitors of the indoleamine 2,3-dioxygenase enzyme and are in clinical trials for various cancers.

See also

References

  1. GRCh38: Ensembl release 89: ENSG00000131203 – Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000031551 – Ensembl, May 2017
  3. “Human PubMed Reference:”. National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. “Mouse PubMed Reference:”. National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Yamazaki F, Kuroiwa T, Takikawa O, Kido R (September 1985). “Human indolylamine 2,3-dioxygenase. Its tissue distribution, and characterization of the placental enzyme”. The Biochemical Journal. 230 (3): 635–8. doi:10.1042/bj2300635. PMC 1152665. PMID 3877502.
  6. “Entrez Gene: INDO indoleamine-pyrrole 2,3 dioxygenase”.
  7. Prendergast GC, Metz R, Muller AJ, Merlo LM, Mandik-Nayak L (2014-11-20). “IDO2 in Immunomodulation and Autoimmune Disease”. Frontiers in Immunology. 5: 585. doi:10.3389/fimmu.2014.00585. PMC 4238401. PMID 25477879.
  8. Badawy AA, Bano S (January 2016). “Tryptophan Metabolism in Rat Liver After Administration of Tryptophan, Kynurenine Metabolites, and Kynureninase Inhibitors”. International Journal of Tryptophan Research. 9: 51–65. doi:10.4137/ijtr.s38190. PMC 4982523. PMID 27547037.
  9. Yoshida R, Hayaishi O (August 1978). “Induction of pulmonary indoleamine 2,3-dioxygenase by intraperitoneal injection of bacterial lipopolysaccharide”. Proceedings of the National Academy of Sciences of the United States of America. 75 (8): 3998–4000. Bibcode:1978PNAS…75.3998Y. doi:10.1073/pnas.75.8.3998. PMC 392917. PMID 279015.
  10. Yoshida R, Urade Y, Tokuda M, Hayaishi O (August 1979). “Induction of indoleamine 2,3-dioxygenase in mouse lung during virus infection”. Proceedings of the National Academy of Sciences of the United States of America. 76 (8): 4084–6. Bibcode:1979PNAS…76.4084Y. doi:10.1073/pnas.76.8.4084. PMC 383982. PMID 291064.
  11. Munn DH, Mellor AL (March 2013). “Indoleamine 2,3 dioxygenase and metabolic control of immune responses”. Trends in Immunology. 34 (3): 137–43. doi:10.1016/j.it.2012.10.001. PMC 3594632. PMID 23103127.
  12. Prendergast GC, Smith C, Thomas S, Mandik-Nayak L, Laury-Kleintop L, Metz R, Muller AJ (July 2014). “Indoleamine 2,3-dioxygenase pathways of pathogenic inflammation and immune escape in cancer”. Cancer Immunology, Immunotherapy. 63 (7): 721–35. doi:10.1007/s00262-014-1549-4. PMC 4384696. PMID 24711084.
  13. Munn DH, Mellor AL (March 2016). “IDO in the Tumor Microenvironment: Inflammation, Counter-Regulation, and Tolerance”. Trends in Immunology. 37 (3): 193–207. doi:10.1016/j.it.2016.01.002. PMC 4916957. PMID 26839260.
  14. Uyttenhove C, Pilotte L, Théate I, Stroobant V, Colau D, Parmentier N, et al. (October 2003). “Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase”. Nature Medicine. 9 (10): 1269–74. doi:10.1038/nm934. PMID 14502282. S2CID 10618102.
  15. Romani L, Fallarino F, De Luca A, Montagnoli C, D’Angelo C, Zelante T, et al. (January 2008). “Defective tryptophan catabolism underlies inflammation in mouse chronic granulomatous disease”. Nature. 451 (7175): 211–5. Bibcode:2008Natur.451..211R. doi:10.1038/nature06471. PMID 18185592. S2CID 4391121.
  16. Mellor AL, Lemos H, Huang L (2017-10-27). “Indoleamine 2,3-Dioxygenase and Tolerance: Where Are We Now?”. Frontiers in Immunology. 8: 1360. doi:10.3389/fimmu.2017.01360. PMC 5663846. PMID 29163470.
  17. MacKenzie CR, Hadding U, Däubener W (September 1998). “Interferon-gamma-induced activation of indoleamine 2,3-dioxygenase in cord blood monocyte-derived macrophages inhibits the growth of group B streptococci”. The Journal of Infectious Diseases. 178 (3): 875–8. doi:10.1086/515347. PMID 9728563.
  18. Adams O, Besken K, Oberdörfer C, MacKenzie CR, Takikawa O, Däubener W (March 2004). “Role of indoleamine-2,3-dioxygenase in alpha/beta and gamma interferon-mediated antiviral effects against herpes simplex virus infections”. Journal of Virology. 78 (5): 2632–6. doi:10.1128/jvi.78.5.2632-2636.2004. PMC 369218. PMID 14963171.
  19. Obojes K, Andres O, Kim KS, Däubener W, Schneider-Schaulies J (June 2005). “Indoleamine 2,3-dioxygenase mediates cell type-specific anti-measles virus activity of gamma interferon”. Journal of Virology. 79 (12): 7768–76. doi:10.1128/jvi.79.12.7768-7776.2005. PMC 1143631. PMID 15919929.
  20. Munn DH, Zhou M, Attwood JT, Bondarev I, Conway SJ, Marshall B, et al. (August 1998). “Prevention of allogeneic fetal rejection by tryptophan catabolism”. Science. 281 (5380): 1191–3. Bibcode:1998Sci…281.1191M. doi:10.1126/science.281.5380.1191. PMID 9712583.
  21. Moon YW, Hajjar J, Hwu P, Naing A (2015). “Targeting the indoleamine 2,3-dioxygenase pathway in cancer”. Journal for Immunotherapy of Cancer. 3: 51. doi:10.1186/s40425-015-0094-9. PMC 4678703. PMID 26674411.
  22. Munn, David H.; Shafizadeh, Ebrahim; Attwood, John T.; Bondarev, Igor; Pashine, Achal; Mellor, Andrew L. (1999-05-03). “Inhibition of T Cell Proliferation by Macrophage Tryptophan Catabolism”. The Journal of Experimental Medicine. 189 (9): 1363–1372. doi:10.1084/jem.189.9.1363. ISSN 0022-1007. PMC 2193062. PMID 10224276.
  23. Frumento, Guido; Rotondo, Rita; Tonetti, Michela; Damonte, Gianluca; Benatti, Umberto; Ferrara, Giovanni Battista (2002-08-12). “Tryptophan-derived Catabolites Are Responsible for Inhibition of T and Natural Killer Cell Proliferation Induced by Indoleamine 2,3-Dioxygenase”. The Journal of Experimental Medicine. 196 (4): 459–468. doi:10.1084/jem.20020121. ISSN 1540-9538. PMC 2196046. PMID 12186838.
  24. Okamoto, Aikou; Nikaido, Takashi; Ochiai, Kazunori; Takakura, Satoshi; Takao, Miho; Saito, Misato; Aoki, Yuko; Ishii, Nobuya; Yanaihara, Nozomu; Yamada, Kyosuke; Takikawa, Osamu (November 2007). “Ido serves as a marker of poor prognosis in gene expression profiles of serous ovarian cancer cells”. International Congress Series. 1304: 262–273. doi:10.1016/j.ics.2007.07.053. ISSN 0531-5131.
  25. Inaba, Tomoko; Ino, Kazuhiko; Kajiyama, Hiroaki; Shibata, Kiyosumi; Yamamoto, Eiko; Kondo, Shinji; Umezu, Tomokazu; Nawa, Akihiro; Takikawa, Osamu; Kikkawa, Fumitaka (June 2010). “Indoleamine 2,3-dioxygenase expression predicts impaired survival of invasive cervical cancer patients treated with radical hysterectomy”. Gynecologic Oncology. 117 (3): 423–428. doi:10.1016/j.ygyno.2010.02.028. ISSN 0090-8258. PMID 20350764.
  26. Uyttenhove, Catherine; Pilotte, Luc; Théate, Ivan; Stroobant, Vincent; Colau, Didier; Parmentier, Nicolas; Boon, Thierry; Van den Eynde, Benoît J (2003-09-21). “Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase”. Nature Medicine. 9 (10): 1269–1274. doi:10.1038/nm934. ISSN 1078-8956. PMID 14502282. S2CID 10618102.
  27. Jiang, Tianze; Sun, Yingying; Yin, Zhichao; Feng, Sen; Sun, Liping; Li, Zhiyu (February 2015). “Research progress of indoleamine 2,3-dioxygenase inhibitors”. Future Medicinal Chemistry. 7 (2): 185–201. doi:10.4155/fmc.14.151. ISSN 1756-8919. PMID 25686005.
  28. Muller, Alexander J; DuHadaway, James B; Donover, P Scott; Sutanto-Ward, Erika; Prendergast, George C (2005-02-13). “Inhibition of indoleamine 2,3-dioxygenase, an immunoregulatory target of the cancer suppression gene Bin1, potentiates cancer chemotherapy”. Nature Medicine. 11 (3): 312–319. doi:10.1038/nm1196. ISSN 1078-8956. PMID 15711557. S2CID 12338548.
  29. Jiang T, Sun Y, Yin Z, Feng S, Sun L, Li Z (2015). “Research progress of indoleamine 2,3-dioxygenase inhibitors”. Future Medicinal Chemistry. 7 (2): 185–201. doi:10.4155/fmc.14.151. PMID 25686005.
  30. Yu CP, Fu SF, Chen X, Ye J, Ye Y, Kong LD, Zhu Z (2018). “The Clinicopathological and Prognostic Significance of IDO1 Expression in Human Solid Tumors: Evidence from a Systematic Review and Meta-Analysis”. Cellular Physiology and Biochemistry. 49 (1): 134–143. doi:10.1159/000492849. PMID 30134237.

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Metabolism: Protein metabolism, synthesis and catabolism enzymes
Oxidoreductases: monooxygenases (EC 1.13)
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