Tryptophan degradation in autoimmune diseases

Opitz, Christiane A.; Wick, Wolfgang; Steinman, Lawrence; Platten, Michael

doi:10.1007/s00018-007-7140-9

Cited by 88 publications

(72 citation statements)

References 212 publications

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“…26 On the other hand, the unique ability of 3-HAA to induce HO-1 is most certainly related to its free radicalgenerating ability because free radicals (reactive oxygen species) provide necessary signals for Nrf2 activation. 73,74 These results then reveal the two-faced nature of 3-HAA in redox regulation. Indeed, Christen et al 75 have previously shown potent antioxidant activities of 3-HAA and 3-HK that were more effective than either ascorbate or vitamin E. They further suggested that the induction of IDO may represent a local antioxidant defense mechanism.…”

Section: Discussionmentioning

confidence: 76%

The Tryptophan Metabolite 3-Hydroxyanthranilic Acid Plays Anti-Inflammatory and Neuroprotective Roles During Inflammation

Krause

Suh

Tarassishin

et al. 2011

The American Journal of Pathology

130

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Tryptophan metabolism by the kynurenine pathway (KP) is important to the pathogenesis of inflammatory, infectious, and degenerative diseases. The 3-hydroxykynurenine (3-HK) branch of the KP is activated in macrophages and microglia, leading to the generation of 3-HK, 3-hydroxyanthranilic acid (3-HAA), and quinolinic acid, which are considered neurotoxic owing to their free radical-generating and N-methyl-D-aspartic acid receptor agonist activities. We investigated the role of 3-HAA in inflammatory and antioxidant gene expression and neurotoxicity in primary human fetal central nervous system cultures treated with cytokines (IL-1 with or without interferon-␥) or with Toll-like receptor ligands mimicking the proinflammatory central nervous system environment. Results were analyzed by microarray, Western blot, immunostain, enzyme-linked immunosorbent assay, and neurotoxicity assays. 3-HAA suppressed glial cytokine and chemokine expression and reduced cytokine-induced neuronal death. 3-HK also suppressed cytokineinduced neuronal death. Unexpectedly, 3-HAA was highly effective in inducing in astrocytes the expression of hemeoxygenase-1 (HO-1), an antioxidant enzyme with anti-inflammatory and cytoprotective properties. Indoleamine-2,3-dioxygenase (IDO) is an interferon (IFN)-␥-inducible, rate-limiting enzyme in the kynurenine pathway (KP) of tryptophan metabolism generating various downstream metabolites collectively termed "kynurenines" 1 ( Figure 1). This process is compartmentalized due to cell-specific expression of the KP enzymes. For example, kynurenine monooxygenase (KMO) is expressed in macrophages and microglia, 2-4 whereas kynurenine aminotransferase II (KAT II) is present in astrocytes.5 A well-appreciated biological activity of IDO is T-cell suppression. IDO expressed in antigen-presenting cells (dendritic cells, macrophages, and microglia) can

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Section: Discussionmentioning

confidence: 76%

The Tryptophan Metabolite 3-Hydroxyanthranilic Acid Plays Anti-Inflammatory and Neuroprotective Roles During Inflammation

Krause

Suh

Tarassishin

et al. 2011

The American Journal of Pathology

130

View full text Add to dashboard Cite

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“…For instance, activation of the mouse and human AHR by agonistic ligands induces regulatory T cells [25][26][27][28] . Mice with a poor-affinity AHR suffer from exacerbated autoimmune encephalomyelitis in the absence of an exogenous ligand 26 , and Trp catabolites suppress autoimmune neuroinflammation 29,30 , suggesting that activation of Trp catabolism represents an endogenous feedback loop to restrict inflammation through the AHR. In fact, exogenous Kyn is involved in the regulation of immune cells in mice through the AHR 31,32 .…”

Section: Article Researchmentioning

confidence: 99%

An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor

Opitz

Litzenburger

Sahm

et al. 2011

Nature

1,513

1,449

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“…As an essential amino acid it cannot be synthesized in humans but has to be taken up with the diet. 1 In addition to serving as a building block for proteins, Trp degradation to kynurenine (Kyn) and downstream metabolites has evolved as a powerful immunoregulatory mechanism 2,3 . In humans Trp degradation is catalyzed by three isoenzymes, indoleamine-2,3-dioxygenase-1 and −2 (IDO1, 2) and tryptophan-2,3-dioxygenase (TDO2).…”

Section: Introductionmentioning

confidence: 99%

Upregulation of tryptophanyl-tRNA synthethase adapts human cancer cells to nutritional stress caused by tryptophan degradation

et al. 2018

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Tryptophan (Trp) metabolism is an important target in immuno-oncology as it represents a powerful immunosuppressive mechanism hijacked by tumors for protection against immune destruction. However, it remains unclear how tumor cells can proliferate while degrading the essential amino acid Trp. Trp is incorporated into proteins after it is attached to its tRNA by tryptophanyl-tRNA synthestases. As the tryptophanyl-tRNA synthestases compete for Trp with the Trp-catabolizing enzymes, the balance between these enzymes will determine whether Trp is used for protein synthesis or is degraded. In human cancers expression of the Trp-degrading enzymes indoleamine-2,3-dioxygenase-1 (IDO1) and tryptophan-2,3-dioxygenase (TDO2) was positively associated with the expression of the tryptophanyl-tRNA synthestase WARS. One mechanism underlying the association between IDO1 and WARS identified in this study is their joint induction by IFNγ released from tumor-infiltrating T cells. Moreover, we show here that IDO1- and TDO2-mediated Trp deprivation upregulates WARS expression by activating the general control non-derepressible-2 (GCN2) kinase, leading to phosphorylation of the eukaryotic translation initiation factor 2α (eIF2α) and induction of activating transcription factor 4 (ATF4). Trp deprivation induced cytoplasmic WARS expression but did not increase nuclear or extracellular WARS levels. GCN2 protected the cells against the effects of Trp starvation and enabled them to quickly make use of Trp for proliferation once it was replenished. Computational modeling of Trp metabolism revealed that Trp deficiency shifted Trp flux towards WARS and protein synthesis. Our data therefore suggest that the upregulation of WARS via IFNγ and/or GCN2-peIF2α-ATF4 signaling protects Trp-degrading cancer cells from excessive intracellular Trp depletion.

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Tryptophan degradation in autoimmune diseases

Cited by 88 publications

References 212 publications

The Tryptophan Metabolite 3-Hydroxyanthranilic Acid Plays Anti-Inflammatory and Neuroprotective Roles During Inflammation

The Tryptophan Metabolite 3-Hydroxyanthranilic Acid Plays Anti-Inflammatory and Neuroprotective Roles During Inflammation

An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor

Upregulation of tryptophanyl-tRNA synthethase adapts human cancer cells to nutritional stress caused by tryptophan degradation

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