Tryptophan metabolism and indoleamine 2,3-dioxygenase expression in coeliac disease

Torres, Marı́a Isabel; López-Casado, Miguel Ángel; Lorite, Pedro; Rı́os, Antonio

doi:10.1111/j.1365-2249.2007.03365.x

Cited by 57 publications

(56 citation statements)

References 31 publications

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“…Elevated levels of neopterin, as well as other monocyte/ macrophage cytokines, in patients with AAV during active disease and remission have also been reported by other groups (13,20,30). Alterations in tryptophan and its metabolites have been shown to contribute to immune regulation in maternal-fetal tolerance (31) and in renal transplant recipients (32), as well as in other autoimmune diseases (33,34). Tryptophan degradation and kynurenine generation are associated with T cell hyporesponsiveness and apoptosis.…”

Section: Discussionmentioning

confidence: 68%

Regulation of myeloperoxidase‐specific T cell responses during disease remission in antineutrophil cytoplasmic antibody–associated vasculitis: The role of Treg cells and tryptophan degradation

Chavele¹,

Shukla²,

Keteepe-Arachi³

et al. 2010

Arthritis & Rheumatism

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Objective. T lymphocytes have been implicated in the pathogenesis of antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Patients with myeloperoxidase (MPO)antineutrophil cytoplasmic antibody (ANCA) experience relapses less frequently than those with proteinase 3 ANCA, suggesting greater immune regulation. This study was undertaken to investigate MPO-specific T cell reactivity during disease remission and the factors regulating their responsiveness.Methods. MPO-specific T cells were quantified by enzyme-linked immunospot assay with additional Treg cell depletion or exogenous interleukin-2. Serum tryptophan and its metabolites were measured. In vivo blockade of indoleamine 2,3-dioxygenase (IDO) was performed, and its effect on MPO reactivity was assessed.Results. During disease remission, MPO-specific interferon-␥-producing T cell frequencies were comparable with those found in healthy controls and significantly lower than those found in patients with acute disease. CD4؉CD25؉ regulatory cells did not play a role in maintaining these low MPO-specific T cell frequencies, since depletion of Treg cells did not augment MPO-specific responses, and FoxP3 levels were diminished in patients compared with controls. Treg cell function, however, was comparable in patients and controls, suggesting numerical rather than functional deficiency. We found diminished serum tryptophan levels and elevated levels of its metabolite kynurenine in patients with MPO AAV as compared with controls. To confirm the effect of tryptophan degradation on MPO responses in vivo, we inhibited degradation in MPOimmunized WKY rats and found greater immune responsiveness to MPO and a tendency to more severe glomerulonephritis.Conclusion. Our findings indicate that MPOspecific T cell frequencies are regulated during disease remission in association with tryptophan degradation. The tryptophan regulatory pathway is induced during active disease and persists during disease remission.The antineutrophil cytoplasmic antibodyassociated vasculitides (AAV) are a group of relapsingremitting systemic diseases that result in considerable morbidity and mortality. Up to 25% of patients develop end-stage renal failure despite optimal immunosuppression. Understanding the immune mechanisms that regulate disease activity is critical for a more successful therapeutic approach to management of the disease. Recent work has highlighted the importance of both humoral and cellular effectors in disease pathogenesis. Pathogenic transplacental transfer of antimyeloperoxidase (anti-MPO) antibody to a neonate has been re-

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Section: Discussionmentioning

confidence: 68%

Regulation of myeloperoxidase‐specific T cell responses during disease remission in antineutrophil cytoplasmic antibody–associated vasculitis: The role of Treg cells and tryptophan degradation

Chavele¹,

Shukla²,

Keteepe-Arachi³

et al. 2010

Arthritis & Rheumatism

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“…In the mouse gut, IDO expression is the highest in the small intestine and is ∼10-fold lower in the cecum and colon (10). Previous studies have shown that IDO expression is elevated in a number of intestinal inflammatory conditions, including ulcerative colitis, Crohn's disease, and celiac disease (25,26), suggesting a need for further investigation of the role of IDO in intestinal inflammation. In this regard, Gurtner et al (15) showed that the IDO inhibitor 1-mT significantly increased the severity of TNBS-induced colitis in mice.…”

Section: Discussionmentioning

confidence: 99%

IDO1 Plays an Immunosuppressive Role in 2,4,6-Trinitrobenzene Sulfate–Induced Colitis in Mice

Takamatsu

Hirata

Ohtaki

et al. 2013

The Journal of Immunology

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IDO, an enzyme that degrades the essential amino acid l-tryptophan to N-formylkynurenine, is known to exert immunomodulatory effects in a number of diseases and disorders. IDO expression is increased in tumors, where it is thought to be involved in tumor evasion by suppressing the immune response. A competitive inhibitor of IDO is currently being tested in clinical trials for relapsed or refractory solid tumors; however, there remains a concern that attenuation of the immunosuppressive function of IDO might exacerbate inflammatory responses. In this study, we investigated the role of IDO in 2,4,6-trinitrobenzene sulfate (TNBS)–induced colitis in mice by gene deletion and pharmacological inhibition. TNBS treatment induced significantly more severe colitis in Ido1 gene–deficient (Ido1−/−) mice than in Ido1 wild-type (Ido1+/+) mice, indicating a role for IDO1 in suppression of acute colitis. Consistent with this, the expression of Ido1 was increased in the colonic interstitial tissues of TNBS-treated Ido1+/+ mice. Furthermore, transplantation of Ido1+/+ bone marrow cells into Ido1−/− mice reduced the pathological damage associated with colitis, altered the expression of cytokines, including IFN-γ, TNF-α, and IL-10, and increased the number of CD4+ Foxp3+ regulatory T cells in the colon. Pharmacological inhibition of IDO enzymatic activity by oral administration of 1-methyltryptophan (1-methyl-l-tryptophan or 1-methyl-d-tryptophan) significantly increased the severity of TNBS-induced colitis in mice, demonstrating that both stereoisomers can promote colitis. Collectively, our data indicate that IDO1 plays an important immunoregulatory role in the colon.

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“…Tryptophan metabolism has been linked to autoimmune disorders associated with inflammation and immune activation [44] . The expression of key genes (Indo and Wars) in tryptophan oxidation increased in the inflamed colon of Il10 -/-mice fed the OA diet.…”

Section: Inflammation and Tryptophan Metabolismmentioning

confidence: 99%

Genome-Wide Analysis of Dietary Eicosapentaenoic Acid- and Oleic Acid-Induced Modulation of Colon Inflammation in Interleukin-10 Gene-Deficient Mice

et al. 2008

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Background/Aims: Dietary n–3 polyunsaturated fatty acids can reduce inflammation via a range of mechanisms. This study tested the effect of dietary eicosapentaenoic acid (EPA) on intestinal inflammation using interleukin-10 gene-deficient (Il10^–/–) mice. Methods: At 35 days of age, 12 weaned Il10^–/– and 12 C57 mice were randomly assigned to one of two modified AIN-76A diets, supplemented with 3.7% purified ethyl esters of either EPA (n–3) or oleic acid (OA, control). To identify genes relevant to colon inflammation, transcription profiling (microarrays and qRT-PCR) and bioinformatic analyses were used. Results: In this study, dietary EPA reversed the decrease in colon fatty acid β-oxidation gene expression observed in OA-fed Il10^–/– compared to C57 mice. Il10^–/– mice fed the OA diet showed decreased expression of antioxidant enzyme genes, as well as those involved in detoxification of xenobiotics, compared to C57 mice on the same diet. In contrast, dietary EPA increased the expression of these genes in Il10^–/– mice. Conclusions: These data indicate that dietary EPA-induced endogenous lipid oxidation which might have a potential anti-inflammatory effect on colon tissue. This is supported by the activation of the Ppara gene that regulates the expression of pro-inflammatory and immunomodulatory genes and proteins.

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Tryptophan metabolism and indoleamine 2,3-dioxygenase expression in coeliac disease

Cited by 57 publications

References 31 publications

Regulation of myeloperoxidase‐specific T cell responses during disease remission in antineutrophil cytoplasmic antibody–associated vasculitis: The role of Treg cells and tryptophan degradation

Regulation of myeloperoxidase‐specific T cell responses during disease remission in antineutrophil cytoplasmic antibody–associated vasculitis: The role of Treg cells and tryptophan degradation

IDO1 Plays an Immunosuppressive Role in 2,4,6-Trinitrobenzene Sulfate–Induced Colitis in Mice

Genome-Wide Analysis of Dietary Eicosapentaenoic Acid- and Oleic Acid-Induced Modulation of Colon Inflammation in Interleukin-10 Gene-Deficient Mice

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