Indoleamine 2,3-Dioxygenase Activity Increases NAD+ Production in IFN-γ–Stimulated Human Primary Mononuclear Cells
Open accessAbstract
IFN-γ activation of mononuclear phagocytes significantly increases indoleamine 2,3-dioxygenase (IDO) and flux through the kynurenine pathway (KP). However, the effect of IDO on NAD+ synthesis, the end product of KP metabolism, is unknown. To investigate this, primary human peripheral blood mononuclear cells were cultured up to 10 days and activated with IFN-γ in the presence or absence of a poly(ADP-ribose) polymerase (PARP) inhibitor. Day 10 macrophages had significantly higher NAD+ levels compared with monocytes. IFN-γ activation of macrophages resulted in the highest induction of IDO but decreased intracellular NAD+ concentrations at both 24 and 48 hours. However, IFN-γ activation of both day 6 and day 10 macrophages in the presence of a PARP inhibitor resulted in significantly higher intracellular NAD+ levels at 24 hours. This study provides evidence for the first time that an immune-mediated increase in IDO activity increases NAD+ biosynthesis concomitantly with an increase in NAD+ catabolism in primary human macrophages.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
QUIN is transiently produced and metabolized into NAD+ in response to inflammation and infection.
“Furthermore, QUIN is transiently produced and metabolized into NAD+ in response to inflammation and infection [59,60].”
From VEEV TC-83 Triggers Dysregulation of the Tryptophan–Kynurenine Pathway in the Central Nervous System That Correlates with Cognitive Impairment in Tg2576 Mice (2024) · cites this paper as [59]
The Results section (page unavailable) reports increased QUIN after 48 hours of IFN-γ stimulation in human monocytes and macrophages. The Discussion identifies QUIN as an NAD precursor, but the paper does not establish that its production is transient or show this response during infection. (LLM, conf=0.85)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Macrophage activation and polarization
Martinez, F. O. (2008) · Frontiers in Bioscience · doi:10.2741/2692 · Cited by 3,160 · see citing works
Tryptophan and the immune response
Moffett, J., & Namboodiri, M. (2003) · Immunology and Cell Biology · doi:10.1046/j.1440-1711.2003.t01-1-01177.x · Cited by 765 · see citing works
Activation of human macrophages. Comparison of other cytokines with interferon-gamma
Nathan, C., Prendergast, T., Wiebe, M., Stanley, E., Platzer, E., Remold, H., Welte, K., Rubin, B. Y., & Murray, H. (1984) · Journal of Experimental Medicine · doi:10.1084/jem.160.2.600 · Cited by 367 · see citing works
Trial watch: IDO inhibitors in cancer therapy
Vacchelli, E., Aranda, F., Eggermont, A. M. M., Sautès‐Fridman, C., Tartour, É., Kennedy, E. P., Platten, M., Zitvogel, L., Kroemer, G., & Galluzzi, L. (2014) · OncoImmunology · doi:10.4161/21624011.2014.957994 · Cited by 327 · see citing works
Characteristics of interferon induced tryptophan metabolism in human cells in vitro.
Werner-Felmayer, G., Werner, E., Fuchs, D., Hausen, A., Reibnegger, G., & Wachter, H. (1989) · Biochimica et Biophysica Acta · doi:10.1016/0167-4889(89)90087-6 · Cited by 210 · see citing works
Mackenzie, C., Heseler, K., Müller, A., & Däubener, W. (2007) · Current drug metabolism · doi:10.2174/138920007780362518 · Cited by 150 · see citing works
Kazazi, F., Mathijs, J., Foley, P., & Cunningham, A. L. (1989) · Journal of General Virology · doi:10.1099/0022-1317-70-10-2661 · Cited by 147 · see citing works
Interferon‐lnduced Indoleamine 2,3‐Dioxygenase Activity in Human Mononuclear Phagocytes
Carlin, J. M., Borden, E. C., Sondel, P., & Byrne, G. I. (1989) · Journal of Leukocyte Biology · doi:10.1002/jlb.45.1.29 · Cited by 144 · see citing works
Human monocyte adherence to cultured vascular endothelium: monoclonal antibody-defined mechanisms.
Wallis, W., Beatty, P., Ochs, H., & Harlan, J. (1985) · Journal of Immunology · doi:10.4049/jimmunol.135.4.2323 · Cited by 124
Macrophages: current views on their differentiation, structure, and function.
Papadimitriou, J. M., & Ashman, R. B. (1989) · Ultrastructural Pathology · doi:10.3109/01913128909048488 · Cited by 120 · see citing works
Grant, R., & Kapoor, V. (1998) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1998.70041759.x · Cited by 91 · see citing works
Self-citationKynurenine pathway inhibition reduces neurotoxicity of HIV-1-infected macrophages
Kerr, S., Armati, P., Pemberton, L., Smythe, G., Tattam, B. N., & Brew, B. (1997) · Neurology · doi:10.1212/wnl.49.6.1671 · Cited by 91 · see citing works
Grant, R., Naif, H. M., Espinosa, M., & Kapoor, V. (2000) · Redox Report · doi:10.1179/135100000101535357 · Cited by 76 · see citing works
Self-citationNaif, H. M., Li, S., Ho-Shon, M., Mathijs, J., Williamson, P., & Cunningham, A. (1997) · Journal of Immunology · doi:10.4049/jimmunol.158.1.501 · Cited by 73
Grant, R., Passey, R. J., Matanovic, G., Smythe, G., & Kapoor, V. (1999) · Archives of Biochemistry and Biophysics · doi:10.1006/abbi.1999.1381 · Cited by 65 · see citing works
Self-citationOrhan, F., Bhat, M., Sandberg, K., Ståhl, S., Piehl, F., Karolinska Schizophrenia Project (KaSP) consortium, Svensson, C., Erhardt, S., & Schwieler, L. (2016) · Scandinavian Journal of Immunology · doi:10.1111/sji.12479 · Cited by 47 · see citing works
Berton, G., Sorio, C., Laudanna, C., Menegazzi, M., de Prati, A. C., & Suzuki, H. (1991) · Biochimica et Biophysica Acta · doi:10.1016/0167-4889(91)90228-p · Cited by 25
Gene expression reprogramming protects macrophage from septic-induced cell death.
Melo, E. S., Barbeiro, D., Gorjão, R., Rios, E., Vasconcelos, D., Velasco, I., Szabó, C., Curi, R., de Lima-Salgado, T. M., & Soriano, F. (2010) · Molecular Immunology · doi:10.1016/j.molimm.2010.06.011 · Cited by 24
Hara, T., Yamakura, F., Takikawa, O., Hiramatsu, R., Kawabe, T., Isobe, K., & Nagase, F. (2008) · JIM - Journal of Immunological Methods · doi:10.1016/j.jim.2007.11.010 · Cited by 13 · see citing works
Cytokine and drug modulation of kynurenine pathway metabolism by blood mononuclear cells.
Saito, K., Seishima, M., Noma, A., Markey, S., & Heyes, M. (1996) · Advances in Experimental Medicine and Biology · doi:10.1007/978-1-4613-0381-7_26 · Cited by 12 · see citing works
Ross, V. (1957) · Archives of Biochemistry and Biophysics · doi:10.1016/0003-9861(57)90167-4 · Cited by 4 · see citing works
Flagged first, then by citations
1 of the 22 references couldn’t be matched to a known paper.
Research works printed but not linked: 1
- [15]Grant RS Passey R Matanovic G Smythe G Kapoor V. Evidence for increased de novo synthesis of NAD in immune-activated RAW264.7 macrophages: a self-protective mechanism? Arch Biochem Biophys. 1999; 372: 1– 7. 10562410
Cited by
Sorted by citations
Role of IDO and TDO in Cancers and Related Diseases and the Therapeutic Implications
Ye, Z., Yue, L., Shi, J., Shao, M., & Wu, T. (2019) · Journal of Cancer · doi:10.7150/jca.31727 · Cited by 215 · see citing works
“(3) MDSCs induction: IDO facilitates MDSCs suppressive function by changing inflammation condition, such as activating IL-6, to suppress CD8+T cells and NK cells as well as induce cancer migration [13].”
BackgroundKynurenine pathway in Parkinson's disease—An update
Venkatesan, D., Iyer, M., Narayanasamy, A., Siva, K., & Vellingiri, B. (2020) · eNeurologicalSci · doi:10.1016/j.ensci.2020.100270 · Cited by 112 · see citing works
IDO/kynurenine pathway in cancer: possible therapeutic approaches
El-Fattah, E. A. A. (2022) · Journal of Translational Medicine · doi:10.1186/s12967-022-03554-w · Cited by 96 · see citing works
“IDO and cancer energetics (NAD) Using human MDMs has provided evidence that indicates that an immune-mediated increase in IDO activity does increase NAD biosynthesis concomitantly with an increase in NAD catabolism [52] (Fig.”
BackgroundMoffett, J. R., Arun, P., Puthillathu, N., Vengilote, R., Ives, J. A., Badawy, A. A.-B., & Namboodiri, A. M. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00031 · Cited by 89 · see citing works
“However, a PARP inhibitor resulted in an increase in NAD levels in macrophages and INF-γ plus the PARP inhibitor further increased NAD levels (14).”
BackgroundTryptophan: A Rheostat of Cancer Immune Escape Mediated by Immunosuppressive Enzymes IDO1 and TDO
Kim, M., & Tomek, P. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.636081 · Cited by 89 · see citing works
The kynurenine pathway in chronic diseases: a compensatory mechanism or a driving force?
Joisten, N., Ruas, J. L., Braidy, N., Guillemin, G. J., & Zimmer, P. (2021) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2021.07.006 · Cited by 97 · see citing works
Lee, L. Y., Oldham, W., He, H., Wang, R.-S., Mulhern, R., Handy, D., & Loscalzo, J. (2021) · Circulation · doi:10.1161/circulationaha.121.053960 · Cited by 84 · see citing works
Joisten, N., Walzik, D., Metcalfe, A. J., Bloch, W., & Zimmer, P. (2020) · International Journal of Tryptophan Research · doi:10.1177/1178646920938688 · Cited by 42 · see citing works
Yang, P., & Zhang, J. (2023) · Biomedicines · doi:10.3390/biomedicines11071988 · Cited by 27 · see citing works
“A recent study demonstrated for the first time that an increase in immune-mediated IDO activity increases not only NAD+ biosynthesis but also NAD+ catabolism in primary human macrophages [43].”
BackgroundMethodAngioni, S. L., Congiu, F., Vitale, S. G., D’Alterio, M. N., Noto, A., Monni, G., Santoru, M. L., Fanos, V., Murgia, F., & Atzori, L. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12030922 · Cited by 19 · see citing works
“This can be explained by the increased demand for energy metabolism, redox balance in immune cells, and the requirement of KP metabolites for immune regulatory functions [104,105].”
BackgroundSuchard, M. S., & Savulescu, D. M. (2021) · FEBS Journal · doi:10.1111/febs.15807 · Cited by 23 · see citing works
Meireson, A., Ferdinande, L., Haspeslagh, M., Hennart, B., Allorge, D., Ost, P., Sundahl, N., Spaas, M., Demeyer, A., & Brochez, L. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.736498 · Cited by 17 · see citing works
Hussain, A., Xie, L., Deng, G., & Kang, X. (2023) · Amino Acids · doi:10.1007/s00726-023-03308-y · Cited by 16 · see citing works
“Additionally, IDO promotes the suppression of myeloidderived suppressor cells by altering inflammatory conditions, such as activating IL-6, which inhibits CD8 + T cells and NK cells and promotes cancer migration (Grant 2018).”
BackgroundTargeting of neuroblastoma cells through Kynurenine‐ AHR pathway inhibition
dos Santos, I. L., Mitchell, M., Nogueira, P. A. S., Lafita‐Navarro, M. C., Perez‐Castro, L., Eriom, J., Kilgore, J. A., Williams, N. S., Guo, L. M., Xu, L., et al. (2024) · FEBS Journal · doi:10.1111/febs.17109 · Cited by 7 · see citing works
Kartika, R., Wibowo, H., Purnamasari, D., Pradipta, S., & Larasati, R. (2020) · International Journal of Tryptophan Research · doi:10.1177/1178646920978236 · Cited by 8 · see citing works
Xu, P., Mageswary, U., Nisaa, A. A., Balasubramaniam, S., Samsudin, S., Rusdi, N. I. B. M., Jerip, A. R., Oon, C., Bakar, M. H. A., Rajendran, D., et al. (2025) · Beneficial Microbes · doi:10.1163/18762891-bja00079 · Cited by 7 · see citing works
Zanella, L. G. F. D. A. B. D. (2022) · Journal of Infectious Diseases and Epidemiology · doi:10.23937/2474-3658/1510243 · Cited by 4 · see citing works
“SIRT6 also plays an essential role in stimulating TNF-alpha expression [19,47,107-109].”
BackgroundRostaminejad, M., Rostami, A. M., Behzad‐Behbahani, A., Dehbidi, G. R., & Kalantari, T. (2021) · Molecular Biology Reports · doi:10.1007/s11033-021-06935-4 · Cited by 5 · see citing works
Fongsaran, C., Dineley, K. T., Paessler, S., & Cisneros, I. E. (2024) · Pathogens · doi:10.3390/pathogens13050397 · Cited by 3 · see citing works
“Hence, additional research focusing on the enzymes responsible for catalyzing the production of various KP metabolites, as well as exploring potential KP enzyme inhibitors, which emerge as a promising avenue for therapeutic interventions in neurodegenerative diseases, is warranted.”
BackgroundEffect of hormone therapy on tryptophan metabolism and atherosclerosis among postmenopausal women
Sriprasert, I., Hilser, J. R., Kono, N., Karim, R., Stanczyk, F. Z., Shoupe, D., Hodis, H. N., Mack, W. J., & Allayee, H. (2025) · Climacteric · doi:10.1080/13697137.2025.2509838 · Cited by 2 · see citing works
“Notably, interferon-γ increases IDO activity [41], which is positively correlated with atherosclerosis [14,15].”
Capatina, A., Czechowski, T., Plunkett-Jones, C., Tonon, T., Kourtzelis, I., Lichman, B., Brackenbury, W., Graham, I., & Lagos, D. (2025) · bioRxiv · doi:10.1042/bcj20253246 · Cited by 2 · see citing works
“Energetically, the kynurenine pathway ultimately generates de novo NAD + molecules, thus contributing to the growth and survival of IDO1-expressing cells [22].”
Chen, M., Lu, Z., Zhang, T., Li, G., Zheng, Q., & Zhang, T. (2026) · Natural Products and Bioprospecting · doi:10.1007/s13659-025-00582-z · Cited by 1 · see citing works
“Certain cells have an increased demand for NAD + during inflammation, injury and infection [46, 47].”
Winkel, P. P., Bergmann-Ewert, W., Reiner, J., Huth, A., Kleimeier, D., Garduño, R. C., Wrobel, I. M., Domańska, G., Däbritz, J., & Wirthgen, E. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1663713
“NAD + is required in the mitochondria for energy production through oxidative phosphorylation (OXPHOS), among other metabolites (41, 42).”
Zanella, L. G. F. D. A. B. D. (2022) · Research Square · doi:10.21203/rs.3.rs-1643416/v1
- Authors
- Grant, R. S.
- Affiliations
- The University of Sydney (AU)
- Corresponding author
- Grant, Ross S
- ORCID
- Grant, Ross S
- Venue
- International Journal of Tryptophan Research
- Publisher
- SAGE Publications
- Published
- 2018-01-01
- Volume
- 11
- Pages
- 1178646917751636-1178646917751636
- ISSN
- 1178-6469 (ISSN-L)
- PMC
- PMC5764136
- OpenAlex
- W2782960396
- Cited by
- 22
- References
- 22
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 2 · 2023: 3 · 2022: 1 · 2021: 6 · 2020: 4 · 2019: 1
- FWCI
- 0.88
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- International Journal of Tryptophan Research (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UNSWorks (University of New South Wales, Sydney, Australia) (submittedVersion, cc-by-nc-nd)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- indoleamine 2,3-dioxygenase, NAD biosynthesis, kynurenine pathway, interferon-gamma, macrophages, monocytes, poly(ADP-ribose) polymerase, tryptophan metabolism, mononuclear phagocytes
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
