Mellor, A. L. & Munn, D. H. Tryptophan catabolism and T-cell tolerance: immunosuppression by starvation? Immunol. Today 20, 469-473

Molecular Immunology Program, Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, GA 30912, USA.
Immunology Today (Impact Factor: 9.49). 11/1999; 20(10):469-73. DOI: 10.1016/S0167-5699(99)01520-0
Source: PubMed


Some macrophages inhibit microbial infections by producing indoleamine 2,3 dioxygenase (IDO), which catabolizes tryptophan. Here, Andrew Mellor and David Munn discuss evidence that cells that synthesize IDO protect the mammalian fetus from maternal T-cell attack and argue that this mechanism might have wider implications for the control of T-cell responses.

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    • "IFN-γ, IL-6 and TNF-α increase the expression of indoleamine-2,3-dioxygenase (IDO) in immune-competent cells (35), an enzyme that can degrade tryptophan and may thereby lead to depressive symptoms (36). Our findings supported the association between elevations of proinflammatory cytokines such as IL-6 and TNF-α and major depression (4, 32). "
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    ABSTRACT: Background: Severe depression may be accompanied by immune dysregulation and is also associated with increased risk of coronary artery disease (CAD). Objectives: We investigated serum levels of 10 cytokines and their relationship with depression in patients with cardiovascular diseases as well as healthy subjects in northeast of Iran. Patients and Methods: The study was carried out on 462 subjects (120 healthy subjects and 342 candidates undergoing angiography). The healthy subjects were referred for routine annual checkups or pre-employment examinations; they did not have clinically evident CAD. A questionnaire was used to obtain demographic data and the Beck depression inventory (BDI) was applied to assess depression. The Evidence Investigator® platform was used for cytokines assays for IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, TNF-α, MCP-1 and IFN-γ, using sandwich chemiluminescent method. The statistical analysis was performed using SPSS version 11.5. Results: The mean age was 53.3 ± 11.5, 54.8 ± 11.3, and 59.5 ± 11.3 in healthy, angiography (-), and angiography (+) subjects, respectively (P < 0.05). There were significant differences in serum levels of IL-4, IL-6, IL-10, and MCP-1 cytokines, comparing subjects with CAD and healthy persons (P < 0.05). When all subjects were divided to with and without depression regardless of their cardiovascular status, there was a significant difference in serum levels of IL-8 and IL-6 between the groups (P < 0.05). When the subgroup with features of CAD was selected and divided to those with and without depression, there was also a significant difference in serum levels of IL-8 and TNF-α (P < 0.05). Conclusions: The positive interaction between depression and CAD was probably mediated by inflammatory mechanisms.
    Full-text · Article · Jul 2014
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    • "It was proposed that the impaired glial–neuronal network induced by imbalanced KYN might contribute to the pathophysiology of psychiatric disorders. The pro-inflammatory status in psychiatric disorders such as major depression would activate the enzymes IDO (Carlin et al., 1987; Yasui et al., 1986) and KMO (Mellor and Munn, 1999). This might result in the reduced tryptophan availability for serotonin synthesis and the shift in the KYN pathway to the arm of 3HK and QUIN with possible reduction in KYNA formation (Fig. 2). "
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    ABSTRACT: The involvement of immune system activation in the pathophysiology of certain psychiatric disorders is well documented. Inflammatory molecules such as pro-inflammatory cytokines could enhance the activity of the indoleamine 2,3-dioxygenase (IDO) enzyme which is the first rate-limiting enzyme of the tryptophan degradation pathway, the kynurenine pathway. The increased tryptophan degradation could induce serotonin depletion and depressive mood. On the other hand, the downstream metabolites from this pathway, such as 3-hydroxykynurenine, quinolinic acid and kynurenic acid, are neuroactive metabolites which can modulate several neurotransmissions, such as glutamatergic, GABAergic, dopaminergic and noradrenergic neurotransmissions, which in turn induce changes in neuronal-glial network and neuropsychiatric consequences. In this issue, we have revised the previous 'neurodegeneration hypothesis,' which explained the involvement of cytokines and IDO pathway interaction in depression, with a further extended view related to the network beyond IDO, the network between immune molecules, tryptophan metabolites and different neurotransmitters, in depression and other major psychiatric disorders such as schizophrenia, bipolar disorder and childhood psychiatric disorders.
    Full-text · Article · Oct 2013 · Progress in Neuro-Psychopharmacology and Biological Psychiatry
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    • "In vitro cultivated NSPCIL-10 and NSPCs expressed large amounts of IDO as demonstrated by RT-PCR (Figure 6a). Inhibition of IDO by the tryptophan analogue 1-MT [26] did not alter the ability of NSPCIL-10 to inhibit polyclonal T-cell proliferation, indicating that immunosuppression by NSPCIL-10 is not mediated by IDO (Figure 6b). "
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    ABSTRACT: Neural stem/progenitor cells (NSPCs) have the ability to migrate into the central nervous system (CNS) to replace damaged cells. In inflammatory CNS disease, cytokine transduced neural stem cells may be used as vehicles to specifically reduce inflammation and promote cell replacement. In this study, we used NSPCs overexpressing IL-10, an immunomodulatory cytokine, in an animal model for CNS inflammation and multiple sclerosis (MS). Intravenous injection of IL-10 transduced neural stem/progenitor cells (NSPCIL-10) suppressed myelin oligodendrocyte glycoprotein aa 35--55 (MOG35-55)- induced experimental autoimmune encephalomyelitis (EAE) and, following intravenous injection, NSPCIL-10 migrated to peripheral lymphoid organs and into the CNS. NSPCIL-10 suppressed antigen-specific proliferation and proinflammatory cytokine production of lymph node cells obtained from MOG35-55 peptide immunized mice. In this model, IL-10 producing NSPCs act via a peripheral immunosuppressive effect to attenuate EAE.
    Full-text · Article · Sep 2013 · Journal of Neuroinflammation
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