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The Role of Indoleamine 2, 3-Dioxygenase in Immune Suppression and Autoimmunity
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Indoleamine 2, 3-dioxygenase (IDO) is the first and rate limiting catabolic enzyme in the degradation pathway of the essential amino acid tryptophan. By cleaving the aromatic indole ring of tryptophan, IDO initiates the production of a variety of tryptophan degradation products called “kynurenines” that are known to exert important immuno-regulatory functions. Because tryptophan must be supplied in the diet, regulation of tryptophan catabolism may exert profound effects by activating or inhibiting metabolism and immune responses. Important for survival, the regulation of IDO biosynthesis and its activity in cells of the immune system can critically alter their responses to immunological insults, such as infection, autoimmunity and cancer. In this review, we assess how IDO-mediated catabolism of tryptophan can modulate the immune system to arrest inflammation, suppress immunity to cancer and inhibit allergy, autoimmunity and the rejection of transplanted tissues. Finally, we examine how vaccines may enhance immune suppression of autoimmunity through the upregulation of IDO biosynthesis in human dendritic cells.
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![Figure 2 Mechanism of IDO1 induction in dendritic cells: transcription and translation. Several molecular stimuli and signaling pathways were shown to induce the transcription and translation of metabolically-active IDO1 enzyme [35,40,50]. The IDO1 promoter contains nucleotide sequences that allow regulation of transcription through interferon sequence response-like element (ISRE) upstream consensus sequences, GAS (palindromic gamma-activated sequences) and non-canonical nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) [42,50]. In addition, the IDO1 promoter region contains three partial non-canonical RelB/p52 binding sites: AGGAGACACA, GGGAGACAGA and AGGAGAAAGA located near position −2000, which is located downstream of NF-κB-driven IDO upregulation following stimulation of the TLR4, INFGR, IFNAR, TNFR and CD40R signaling pathways [43].](/paper-figures/c748b5e2d686409aba397c4eb47122fd/the-role-of-indoleamine-2-3-dioxygenase-in-immune-suppression-and-autoimmunity-figure-2.jpg)
![Figure 3 The TGF-β-IDO-SHP axis. The TGF-β-IDO-SHP axis activates the non-canonical NF-κB pathway [49]. In splenocytes, SHP-1 inhibits the protein kinase IRAK1 and tips the balance of activation of the canonical versus non-canonical NF-κB signaling pathway in favor of the latter, resulting in upregulated production of type I interferon [49]. In addition to TGF-β, the aryl hydrocarbon receptor (AhR) has also been shown to play a role in IDO production [51,53]. Interestingly, kynurenines produced from IDO’s enzymatic activity can also bind and activate as an endogenous ligand, AhR [53,54]. Abbreviations: IFN (α β, γ,): interferon alpha, beta, gamma; TGF-β: transforming growth factor-beta; TNF: tumor necrosis factor; TLR4: toll-like receptor 4; TRAF: TNF-receptor associated factors; TRIF: TIR-domain-containing adapter-inducing interferon-β; SHP: orphan nuclear receptor small heterodimer partner; SMAD: extracellular signal transducers from TGF-β ligands to the nucleus; IRF (1, 3): and interferon regulatory factor 1,3.](/paper-figures/ded76164a88e4dc388ba105d8aa15574/the-role-of-indoleamine-2-3-dioxygenase-in-immune-suppression-and-autoimmunity-figure-3.jpg)
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“Increased IDO expression is responsible for the catabolism of TRP in the KYN degradation pathway [36] and is canonically upregulated by inflammatory mechanisms [37,38].”
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“Enzymes Related to Immune Response Indoleamine 2,3-dioxygenase (IDO) IDO is an enzyme that converts the essential amino acid ltryptophan into kynurenine and carries an immunosuppressive effect through multiple mechanisms (80).”
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Indoleamine 2, 3-dioxygenase regulation of immune response (Review)
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“Therefore, we chose an inhibitor of IDO2: 1-D-MT for further research (Novak et al., 1995; Metz et al., 2007).”
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Metabolic Reprogramming in Cancer is Induced to Increase Proton Production.
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Immunosuppressive Amino-Acid Catabolizing Enzymes in Multiple Sclerosis
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“IDO1-dependent suppression of T cell responses has been proposed as an immunoregulatory pathway implicated in maternal tolerance of allogeneic fetuses during mammalian gestation, as well as in tumor tolerance, and protective regulation in autoimmune disease (9, 15, 18).”
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“IDO is stimulated by lipopolysaccharide (LPS), TNFα, IFN-γ, transforming growth factor (TGF)ß and activation of toll-like receptor (TLR)3, TLR4, TLR7, and TLR8 [30].”
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“Page 3/31 regulate the differentiation direction of Th17/Treg cells, thereby promoting the balanced differentiation of Th17/Treg to Treg cells [3-5].”
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“T cells can modulate the activity of endothelial cells through the release of specific cytokines such as theTh1 cytokines IFN-γ and TNF-α, theTh2 cytokines IL-4 and IL-13, and theTreg cytokines IL-10 and TGF-β.”
BackgroundInfluentialTargeting the Kynurenine Pathway for the Treatment of Cisplatin-Resistant Lung Cancer
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Targeting Molecular Inflammatory Pathways in Granuloma as Host-Directed Therapies for Tuberculosis
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“defense against infectious agents, in maternal–fetal tolerance, in oncologic processes as well as in autoimmune diseases (7).”
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“Moreover, it promotes cancer cell survival through enhanced suppression of immunity (99).”
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“In return, when CTLA-4 is induced in Tregs, CTLA-4 mediates the down-regulating of co-stimulatory molecules, CD80 and CD86 on DCs, and thus reduces the potency of APCs to activate other T cells, critically controlling the immunosuppressive activity of Tregs (Figure 2B) [76].”
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Switch of NAD Salvage to de novo Biosynthesis Sustains SIRT1-RelB-Dependent Inflammatory Tolerance
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“Interestingly, although IDO1-NAD pathway plays an important role in sustaining tolerance, it is not required for tolerance induction (26, 31).”
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“MSCs exert an immunosuppressive function in the human body and the molecular mechanisms underlying the MSC-mediated immunosuppression were shown to be species dependent [81–84].”
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“This depletion has been demonstrated to trigger anergy and apoptosis in effector T cells [104].”
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“Tumors that utilize IDO deplete tryptophan from T cells forming kynurenines, which predispose an exhausted and regulatory T cell phenotype [70,71].”
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“…TAMS mediated immunosuppression is to directly inhibit its tumor-promoting function, including inhibiting the production of IDO and thereby inhibiting CTL proliferation [186, 187], and has been associated with peritoneal dissemination and poor survival outcomes in patients with ovarian cancer.”
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“Engineered NPs allowed immune suppression to be reversed by blocking the IDO pathways (Mbongue et al., 2015).”
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“TGF-β can further suppress NK cell activity by recruiting or activating a variety of cancer-promoting immune cells, including Tregs [134], MDSCs [135, 136], CD11bLy6G neutrophils [137], and indoleamine 2,3dioxygenase 1 (IDO1)-expressing dendritic cells (DCs) [138].”
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“Trp, a precursor of kynurenine, is metabolized to kynurenine by the action of indoleamine 2,3-dioxygenase (IDO).(22,23) Under normal physiological conditions, IDO expression is modulated; however, it is often upregulated in several cancer types.”
Background
Metadata
- Authors
- Mbongue, J., Nicholas, D., Torrez, T., Kim, N.-S., Firek, A., & Langridge, W.
- Affiliations
- Loma Linda University (US)
- California Baptist University (US)
- Jerry L. Pettis Memorial VA Medical Center (US)
- Corresponding author
- Langridge, William
- Venue
- Vaccines
- Publisher
- MDPI AG
- Published
- 2015-09-10
- Volume
- 3
- Issue
- 3
- Pages
- 703-729
- ISSN
- 2076-393X (ISSN-L)
- PMC
- PMC4586474
- OpenAlex
- W2101376945
- Cited by
- 351
- References
- 165
- Citations by year
- 2026: 18 · 2025: 32 · 2024: 32 · 2023: 39 · 2022: 43 · 2021: 39 · 2020: 47 · 2019: 34 · 2018: 39 · 2017: 16 · 2016: 11 · 2015: 1
- FWCI
- 1.26
- Type
- journal article
- Language
- en
- Open access
- gold
- dx.doi.org
- Licence
- Locations
- Vaccines (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Loma Linda University
- National Institutes of Health (DK-99-013)
- National Institute of General Medical Sciences (R25GM060507)
- National Institute on Minority Health and Health Disparities (P20MD006988)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- indoleamine 2,3-dioxygenase, tryptophan catabolism, kynurenine, immunosuppression, autoimmunity, dendritic cells, tumor immunosuppression, allergy, graft rejection, inflammation, vaccine adjuvants, tryptophan metabolism
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