Monitoring tryptophan metabolism in chronic immune activation
Abstract
The essential amino acid tryptophan is a constituent of proteins and is also a substrate for two important biosynthetic pathways: the generation of neurotransmitter 5-hydroxytryptamine (serotonin) by tryptophan 5-hydroxylase, and the formation of kynurenine derivatives and nicotinamide adenine dinucleotides. The latter pathway is initiated by the enzymes tryptophan pyrrolase (tryptophan 2,3-dioxygenase, TDO) and indoleamine 2,3-dioxygenase (IDO). TDO is located in liver cells, whereas IDO is expressed in a variety of cells including monocyte-derived macrophages and dendritic cells and is preferentially induced by Th1-type cytokine interferon-gamma. Tryptophan depletion via IDO is part of the cytostatic and antiproliferative activity mediated by interferon-gamma in cells. In vivo tryptophan concentration can be measured by HPLC by monitoring its natural fluorescence (285 nm excitation and 365 nm emission wavelength). IDO activity is characterized best by the kynurenine to tryptophan ratio which correlates with concentrations of immune activation markers such as neopterin. Low serum/plasma tryptophan concentration is observed in infectious, autoimmune, and malignant diseases and disorders that involve cellular (Th1-type) immune activation as well as during pregnancy due to accelerated tryptophan conversion. Thus, in states of persistent immune activation, low tryptophan concentration may contribute to immunodeficiency. Decreased serum tryptophan can also effect serotonin biosyn…
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The KYN/TRP ratio is a reliable indicator for tracking TRP degradation, which further implies enhanced IDO activity.
“The KYN/TRP ratio, particularly when comparing the concentration of IDO’s first product to the substrate, is a reliable indicator for tracking TRP degradation, which further implies enhanced IDO activity [48].”
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“In the blood, IDO stimulation leads to an increase in the formation of l-kynurenine (‘kynurenine’; Schröcksnadel et al., 2006), a pivotal kynurenine pathway metabolite, which is readily transported”
Blumenthal, A., Nagalingam, G., Huch, J. H., Walker, L., Guillemin, G. J., Smythe, G. A., Ehrt, S., Britton, W. J., & Saunders, B. M. (2012) · PLoS ONE · doi:10.1371/journal.pone.0037314 · Cited by 105 · see citing works
“IDO-2 remained unchanged during Plasmodium berghei ANKA infection [46] and TDO activity has also not been associated with immunerelated tryptophan metabolism [47].”
BackgroundIannitti, R., Carvalho, A., Cunha, C., Luca, A. D., Giovannini, G., Casagrande, A., Zelante, T., Vacca, C., Fallarino, F., Puccetti, P., et al. (2013) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201207-1346oc · Cited by 104 · see citing works
“The kynurenine-to-tryptophan ratio was determined as described (28).”
BackgroundMethodEffects of Exhaustive Aerobic Exercise on Tryptophan-Kynurenine Metabolism in Trained Athletes
Strasser, B., Geiger, D., Schauer, M., Gatterer, H., Burtscher, M., & Fuchs, D. (2016) · PLoS ONE · doi:10.1371/journal.pone.0153617 · Cited by 101 · see citing works
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Strasser, B., Becker, K., Fuchs, D., & Gostner, J. M. (2017) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.02.030 · Cited by 97 · see citing works
“A decrease of tryptophan levels and an increase kynurenine to tryptophan ratio (Kyn/Trp) was found in several pathologies that are associated with chronic immune activation (Schroecksnadel et al., 2006), and this decrease was ascribed to inflammation-induced IDO-1 activity.”
InfluentialSelf-citationKynurenine pathway in psychosis: evidence of increased tryptophan degradation
Barry, S., Clarke, G., Scully, P., & Dinan, T. (2009) · Journal of Psychopharmacology · doi:10.1177/0269881108089583 · Cited by 96 · see citing works
Maier, E., Kurz, K., Jenny, M., Schennach, H., Ueberall, F., & Fuchs, D. (2010) · Food and Chemical Toxicology · doi:10.1016/j.fct.2010.04.042 · Cited by 96 · see citing works
Self-citationEnzymology of mammalian NAD metabolism in health and disease
Magni, G. (2008) · Frontiers in bioscience · doi:10.2741/3143 · Cited by 93 · see citing works
Natural Molecules and Neuroprotection: Kynurenic Acid, Pantethine and α-Lipoic Acid
Tóth, F., Cseh, E., & Vécsei, L. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22010403 · Cited by 92 · see citing works
“dioxygenase (IDO) [35] and tryptophan 2,3-dioxygenase (TDO) enzymes [36], the rate-”
BackgroundPain/Depression Dyad: A Key to a Better Understanding and Treatment of Functional Somatic Syndromes
Goldenberg, D. L. (2010) · The American Journal of Medicine · doi:10.1016/j.amjmed.2010.01.014 · Cited by 94 · see citing works
Nguyen, T. V., Alfaro, A. C., Young, T., Ravi, S., & Mérien, F. (2018) · Marine Biotechnology · doi:10.1007/s10126-018-9804-x · Cited by 102 · see citing works
“It is also a substrate for other major biosynthetic routes, such as the synthesis of serotonin, essent ial cel lular factors and the kynurenine pathway (Schröcksnadel et al. 2006).”
BackgroundA tryptophan metabolite, kynurenine, promotes mast cell activation through aryl hydrocarbon receptor
Kawasaki, H., Chang, H. ‐., Tseng, H.-C., Hsu, S., Yang, S. ‐., Hung, C. ‐., Zhou, Y., & Huang, S. (2014) · Allergy · doi:10.1111/all.12346 · Cited by 89 · see citing works
“This latter pathway is initiated by cleavage of the indole ring by two different rate-limiting enzymes: indoleamine 2,3-dioxygenase (IDO) found in many immune cells, such as dendritic cells and macrophages, and tryptophan 2,3-dioxygenase (TDO) located in not only liver and neuron, but also some tumor cells such as mal…”
BackgroundMycobacterium Leprae –Host-Cell Interactions and Genetic Determinants in Leprosy: an Overview
Pinheiro, R. O., Sales, J. D. S., Sarno, E. N., & Sampaio, E. P. (2011) · Future Microbiology · doi:10.2217/fmb.10.173 · Cited by 83 · see citing works
Geisler, S., Mayersbach, P., Becker, K., Schennach, H., Fuchs, D., & Gostner, J. M. (2015) · Pteridines · doi:10.1515/pterid-2014-0015 · Cited by 91 · see citing works
“IDO converts the essential amino acid L-tryptophan (TRP) to kynurenine (KYN), which is the first and rate-limiting step of tryptophan catabolism.”
BackgroundInfluentialSelf-citationJenny, M., Klieber, M., Zaknun, D., Schroecksnadel, S., Kurz, K., Ledochowski, M., Schennach, H., & Fuchs, D. (2010) · Inflammation Research · doi:10.1007/s00011-010-0244-y · Cited by 73 · see citing works
“comparing kyn and kyn/trp in serum or plasma, kyn/trp is certainly superior because of greater variance of trp concentrations in humans [ 16 ].”
BackgroundSelf-citationMidttun, Ø., Ulvik, A., Pedersen, E. R., Ebbing, M., Bleie, Ø., Schartum-Hansen, H., Nilsen, R. M., Nygard, O. K., & Ueland, P. M. (2011) · Journal of Nutrition · doi:10.3945/jn.110.133082 · Cited by 80 · see citing works
Li, T., Fu, B., Zhang, X., Zhou, Y., Yang, M., Cao, M., Chen, Y., Tan, Y., & Hu, R. (2021) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-20-1043 · Cited by 112 · see citing works
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“expressed in the liver in response to TRP, KYN, and glucocorticoids and regulates systemic TRP levels.(28) On the other hand, IDO can be found in various cells throughout”
BackgroundVisceral Inflammation and Immune Activation Stress the Brain
Holzer, P., Farzi, A., Hassan, A. M., Zenz, G., Jačan, A., & Reichmann, F. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01613 · Cited by 84 · see citing works
“These behavioral perturbations are associated with disruption of the BBB, enhanced expression of indoleamine 2,3-dioxygenase (IDO) in hippocampus and 10 Holzer et al. Immune Activation Stresses the Brain Frontiers in Immunology | www.frontiersin.org November 2017 | Volume 8 | Article 1613 frontal cortex, suppression o…”
BackgroundInfluentialChromatographic analysis of tryptophan metabolites
Sadok, I., Gamian, A., & Staniszewska, M. (2017) · Journal of Separation Science · doi:10.1002/jssc.201700184 · Cited by 84 · see citing works
“The neurodegenerative disorders affecting older people can be explained by the observation that [Kyn]/[Trp] ratio correlates with the level of neopterin, an immune activation marker [53] the concentration of which in the central nervous system increases with age in women [54].”
BackgroundTryptophan Metabolism in Allergic Disorders
Gostner, J. M., Becker, K., Kofler, H., Strasser, B., & Fuchs, D. (2016) · International Archives of Allergy and Immunology · doi:10.1159/000445500 · Cited by 92 · see citing works
Self-citationPedersen, E., Svingen, G., Schartum-Hansen, H., Ueland, P., Ebbing, M., Nordrehaug, J., Igland, J., Seifert, R., Nilsen, R. M., & Nygård, O. (2013) · European Heart Journal · doi:10.1093/eurheartj/eht264 · Cited by 84 · see citing works
“Since IDO is not expressed unless stimulated by IFN-g,(5) increased degradation of tryptophan is typically seen in states of activated cellular (Th1) immune responses.(6) Lowered endogenous tryptophan and kynurenine levels, however, occur when dietary intake of tryptophan is restricted.”
BackgroundInfluentialThe role of indoleamine 2,3-dioxygenase in transplantation
Hainz, U., Jürgens, B., & Heitger, A. (2006) · Transplant International · doi:10.1111/j.1432-2277.2006.00370.x · Cited by 59 · see citing works
“In general, enhanced tryptophan degradation is observed in conditions of sustained cellular immune activation [26,44].”
BackgroundAccumulation of an Endogenous Tryptophan-Derived Metabolite in Colorectal and Breast Cancers
Puccetti, P., Fallarino, F., Italiano, A., Soubeyran, I., MacGrogan, G. M., Debled, M., Velasco, V., Bodet, D., Eimer, S., Veldhoen, M., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0122046 · Cited by 87 · see citing works
The Kynurenine Pathway: A Primary Resistance Mechanism in Patients with Glioblastoma.
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“Increased IDO expression and activity are correlated with poor patient prognosis and quality of life [4, 5].”
BackgroundKnock-on effect of periodontitis to the pathogenesis of Alzheimer’s disease?
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Self-citationImaging Correlates of Differential Expression of Indoleamine 2,3-Dioxygenase in Human Brain Tumors
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“In mammals, most of the tryptophan derived from the diet is converted via the kynurenine pathway [36], which is upregulated in several autoimmune disorders and malignant neoplasms [35].”
Amino Acids and Their Metabolism in Atherosclerosis
Nitz, K., Lacy, M., & Atzler, D. (2019) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.118.311572 · Cited by 95 · see citing works
The association between immune activation and manic symptoms in patients with a depressive disorder
Becking, K., Boschloo, L., Vogelzangs, N., Haarman, B. C. M., der Lek, R. F. R., Penninx, B. W. J. H., & Schoevers, R. A. (2013) · Translational Psychiatry · doi:10.1038/tp.2013.87 · Cited by 71 · see citing works
Circulating biomarkers of tryptophan and the kynurenine pathway and lung cancer risk.
Chuang, S., Fanidi, A., Ueland, P., Relton, C., Midttun, Ø., Vollset, S., Gunter, M., Seckl, M., Travis, R., Wareham, N., et al. (2014) · Cancer Epidemiology, Biomarkers and Prevention · doi:10.1158/1055-9965.epi-13-0770 · Cited by 75 · see citing works
“an indirect measure of IDO activity (11, 13).”
Background
- Authors
- Schröcksnadel, K., Wirleitner, B., Winkler, C., & Fuchs, D.
- Affiliations
- Innsbruck Medical University (AT)
- Corresponding author
- Fuchs, Dietmar
- Venue
- Clinica Chimica Acta
- Publisher
- Elsevier BV
- Published
- 2006-02
- Volume
- 364
- Issue
- 1-2
- Pages
- 82-90
- ISSN
- 0009-8981 (ISSN-L)
- OpenAlex
- W2042985653
- Cited by
- 551
- References
- 0
- Citations by year
- 2026: 7 · 2025: 25 · 2024: 19 · 2023: 24 · 2022: 32 · 2021: 47 · 2020: 31 · 2019: 21 · 2018: 27 · 2017: 34 · 2016: 26 · 2015: 32 · 2014: 24 · 2013: 38 · 2012: 36
- FWCI
- 0.80
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinica Chimica Acta (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Immunology and Microbiology › Immunology › Reproductive System and Pregnancy
- Keywords
- tryptophan metabolism, tryptophan depletion, indoleamine 2,3-dioxygenase, tryptophan 2,3-dioxygenase, kynurenine pathway, serotonin synthesis, interferon-gamma, chronic immune activation, Th1 response, neopterin, immunodeficiency, anemia, mood disorders, autoimmune disease, infectious diseases, pregnancy
- MeSH terms
- Autoimmune Diseases, Humans, Infections, Kynurenine, Neoplasms, Serotonin, Tryptophan, Tryptophan Hydroxylase, Tryptophan Oxygenase, Indoleamine-Pyrrole 2,3,-Dioxygenase
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