Indoleamine 2,3-dioxygenase explained

Symbol:IDO
Indoleamine 2,3-dioxygenase
Pfam:PF01231
Pfam Clan:CL0380
Interpro:IPR000898
Prosite:PDOC00684
Indoleamine 2,3-dioxygenase
Ec Number:1.13.11.52
Cas Number:9014-51-1
Go Code:0033754

Indoleamine-pyrrole 2,3-dioxygenase (IDO or INDO) 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.[1] In humans is encoded by the IDO1 gene.[2] 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 -tryptophan to N-formylkynurenine, the others being indolamine-2,3-dioxygenase 2 (IDO2)[3] and tryptophan 2,3-dioxygenase (TDO).[4] IDO is an important part of the immune system and plays a part in natural defense against various pathogens.[5] [6] 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.[7] 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.[8] [9] [10] Furthermore, there is data implicating a role for IDO1 in the modulation of vascular tone in conditions of inflammation via a novel pathway involving singlet oxygen.[11]

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.[12] 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.[13] 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[14] or viruses such as herpes simplex[15] or measles.[16]

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.[17]

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.[18] IDO is known to suppress T and NK cells, generate Tregs and myeloid-derived suppressor cells, and also supports angiogenesis.

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.[19] The second mechanism is based on the production of catabolic products called kynurenins, that are cytotoxic for T lymphocytes and NK cells.[20] Overexpression of human IDO (hIDO) is described in a variety of human tumor cell lineages and is often associated with poor prognosis.[21] [22] Tumors with increased production of IDO include prostate, ovarian, lung or pancreatic cancer or acute myeloid leukemia.[23] [24] Expression of IDO is under physiological conditions regulated by the Bin1 gene, which can be damaged by tumor transformation.[25]

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,[26] as well as efforts to understand if it could be used as a biomarker for prognosis.[27]

Inhibitors

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

1-Methyltryptophan is a racemic compound that weakly inhibits indoleamine dioxygenase, but is also a very slow substrate. The specific racemer 1-methyl--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

External links

Notes and References

  1. Yamazaki F, Kuroiwa T, Takikawa O, Kido R . Human indolylamine 2,3-dioxygenase. Its tissue distribution, and characterization of the placental enzyme . The Biochemical Journal . 230 . 3 . 635–8 . September 1985 . 3877502 . 1152665 . 10.1042/bj2300635 .
  2. Web site: Entrez Gene: INDO indoleamine-pyrrole 2,3 dioxygenase.
  3. Prendergast GC, Metz R, Muller AJ, Merlo LM, Mandik-Nayak L . IDO2 in Immunomodulation and Autoimmune Disease . Frontiers in Immunology . 5 . 585 . 2014-11-20 . 25477879 . 4238401 . 10.3389/fimmu.2014.00585 . free .
  4. Badawy AA, Bano S . Tryptophan Metabolism in Rat Liver After Administration of Tryptophan, Kynurenine Metabolites, and Kynureninase Inhibitors . International Journal of Tryptophan Research . 9 . 51–65 . January 2016 . 27547037 . 4982523 . 10.4137/ijtr.s38190 .
  5. Yoshida R, Hayaishi O . 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 . August 1978 . 279015 . 392917 . 10.1073/pnas.75.8.3998 . 1978PNAS...75.3998Y . free .
  6. Yoshida R, Urade Y, Tokuda M, Hayaishi O . 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 . August 1979 . 291064 . 383982 . 10.1073/pnas.76.8.4084 . 1979PNAS...76.4084Y . free .
  7. Munn DH, Mellor AL . Indoleamine 2,3 dioxygenase and metabolic control of immune responses . Trends in Immunology . 34 . 3 . 137–43 . March 2013 . 23103127 . 3594632 . 10.1016/j.it.2012.10.001 .
  8. Prendergast GC, Smith C, Thomas S, Mandik-Nayak L, Laury-Kleintop L, Metz R, Muller AJ . Indoleamine 2,3-dioxygenase pathways of pathogenic inflammation and immune escape in cancer . Cancer Immunology, Immunotherapy . 63 . 7 . 721–35 . July 2014 . 24711084 . 4384696 . 10.1007/s00262-014-1549-4 .
  9. Munn DH, Mellor AL . IDO in the Tumor Microenvironment: Inflammation, Counter-Regulation, and Tolerance . Trends in Immunology . 37 . 3 . 193–207 . March 2016 . 26839260 . 4916957 . 10.1016/j.it.2016.01.002 .
  10. Uyttenhove C, Pilotte L, Théate I, Stroobant V, Colau D, Parmentier N, Boon T, Van den Eynde BJ . 6 . Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase . Nature Medicine . 9 . 10 . 1269–74 . October 2003 . 14502282 . 10.1038/nm934 . 10618102 .
  11. Stanley CP, Maghzal GJ, Ayer A, Talib J, Giltrap AM, Shengule S et al. . Singlet molecular oxygen regulates vascular tone and blood pressure in inflammation . Nature . 566 . 548–552 . February 2019 . 7745 . 30760924 . 10.1038/s41586-019-0947-3 . 2019Natur.566..548S . 1959.17/169229 . 61156683 .
  12. Romani L, Fallarino F, De Luca A, Montagnoli C, D'Angelo C, Zelante T, Vacca C, Bistoni F, Fioretti MC, Grohmann U, Segal BH, Puccetti P . 6 . Defective tryptophan catabolism underlies inflammation in mouse chronic granulomatous disease . Nature . 451 . 7175 . 211–5 . January 2008 . 18185592 . 10.1038/nature06471 . 2008Natur.451..211R . 4391121 .
  13. Mellor AL, Lemos H, Huang L . Indoleamine 2,3-Dioxygenase and Tolerance: Where Are We Now? . Frontiers in Immunology . 8 . 1360 . 2017-10-27 . 29163470 . 5663846 . 10.3389/fimmu.2017.01360 . free .
  14. MacKenzie CR, Hadding U, Däubener W . 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 . September 1998 . 9728563 . 10.1086/515347 . free .
  15. Adams O, Besken K, Oberdörfer C, MacKenzie CR, Takikawa O, Däubener W . 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 . March 2004 . 14963171 . 369218 . 10.1128/jvi.78.5.2632-2636.2004 .
  16. Obojes K, Andres O, Kim KS, Däubener W, Schneider-Schaulies J . Indoleamine 2,3-dioxygenase mediates cell type-specific anti-measles virus activity of gamma interferon . Journal of Virology . 79 . 12 . 7768–76 . June 2005 . 15919929 . 1143631 . 10.1128/jvi.79.12.7768-7776.2005 .
  17. Munn DH, Zhou M, Attwood JT, Bondarev I, Conway SJ, Marshall B, Brown C, Mellor AL . 6 . Prevention of allogeneic fetal rejection by tryptophan catabolism . Science . 281 . 5380 . 1191–3 . August 1998 . 9712583 . 10.1126/science.281.5380.1191 . 1998Sci...281.1191M .
  18. Moon YW, Hajjar J, Hwu P, Naing A . Targeting the indoleamine 2,3-dioxygenase pathway in cancer . Journal for Immunotherapy of Cancer . 3 . 51 . 2015 . 26674411 . 4678703 . 10.1186/s40425-015-0094-9 . free .
  19. 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. 10.1084/jem.189.9.1363. 10224276. 2193062. 0022-1007. free.
  20. 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. 10.1084/jem.20020121. 12186838. 2196046. 1540-9538. free.
  21. 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. 10.1016/j.ics.2007.07.053. 0531-5131.
  22. 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. 10.1016/j.ygyno.2010.02.028. 20350764. 0090-8258.
  23. 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. 10.1038/nm934. 14502282. 10618102. 1078-8956.
  24. 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. 10.4155/fmc.14.151. 25686005. 1756-8919.
  25. 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. 10.1038/nm1196. 15711557. 12338548. 1078-8956.
  26. 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. 10.4155/fmc.14.151. 25686005.
  27. Yu CP, Fu SF, Chen X, Ye J, Ye Y, Kong LD, Zhu Z . 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 . 2018 . 30134237 . 10.1159/000492849 . free .

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