The tryptophan metabolite 3-hydroxyanthranilic acid suppresses T cell responses by inhibiting dendritic cell activation

Lee, Won-Sik; Lee, Soung-Min; Park, Sae-Gwang; Choi, Ii-Whan; Choi, Inhak; Joo, Young-Don; Park, Sungjae; Kang, Sung Goo; Seo, Su‐Kil

doi:10.1016/j.intimp.2013.08.018

Cited by 46 publications

(30 citation statements)

References 35 publications

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“…In fact, stimulation of MSC with LPS and/or IFN γ induces the expression of several immunosuppressor factors, such as HGF, nitric oxide (NO) and insulin-like growth factor (IGF) and increase Jagged-1, PGE2, and IDO expression [ 25 , 26 , 31 – 33 ]. In line with this, previous studies demonstrated that IL-6 expression might be inhibited by Jagged-1 and HGF in macrophages [ 55 , 58 ], or by IDO in DC [ 53 ], though IDO presents the opposite effect in human cancer cells [ 59 ]. In turn, PGE2 has the ability to impair the expression of CCL3, CCL5, and CXCL10 in human DC, macrophages [ 56 , 60 , 61 ], microglial cells and astrocyes [ 62 ] and of CXCL9 and CXCL10 in human breast cancer cells [ 48 ]; HGF and NO were demonstrated to inhibit CCL5 expression in human renal tubular epithelial cells and in mouse keratinocytes, respectively [ 63 – 65 ], while CXCL10 expression in melanoma cells is downregulated by NO [ 66 ].…”

Section: Discussionsupporting

confidence: 62%

Human Bone Marrow-Derived Mesenchymal Stromal Cells Differentially Inhibit Cytokine Production by Peripheral Blood Monocytes Subpopulations and Myeloid Dendritic Cells

Laranjeira¹,

Gomes

Pedreiro³

et al. 2015

Stem Cells International

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The immunosuppressive properties of mesenchymal stromal/stem cells (MSC) rendered them an attractive therapeutic approach for immune disorders and an increasing body of evidence demonstrated their clinical value. However, the influence of MSC on the function of specific immune cell populations, namely, monocyte subpopulations, is not well elucidated. Here, we investigated the influence of human bone marrow MSC on the cytokine and chemokine expression by peripheral blood classical, intermediate and nonclassical monocytes, and myeloid dendritic cells (mDC), stimulated with lipopolysaccharide plus interferon (IFN)γ. We found that MSC effectively inhibit tumor necrosis factor- (TNF-) α and macrophage inflammatory protein- (MIP-) 1β protein expression in monocytes and mDC, without suppressing CCR7 and CD83 protein expression. Interestingly, mDC exhibited the highest degree of inhibition, for both TNF-α and MIP-1β, whereas the reduction of TNF-α expression was less marked for nonclassical monocytes. Similarly, MSC decreased mRNA levels of interleukin- (IL-) 1β and IL-6 in classical monocytes, CCL3, CCL5, CXCL9, and CXCL10 in classical and nonclassical monocytes, and IL-1β and CXCL10 in mDC. MSC do not impair the expression of maturation markers in monocytes and mDC under our experimental conditions; nevertheless, they hamper the proinflammatory function of monocytes and mDC, which may impede the development of inflammatory immune responses.

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Section: Discussionsupporting

confidence: 62%

Human Bone Marrow-Derived Mesenchymal Stromal Cells Differentially Inhibit Cytokine Production by Peripheral Blood Monocytes Subpopulations and Myeloid Dendritic Cells

Laranjeira¹,

Gomes

Pedreiro³

et al. 2015

Stem Cells International

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“…In contrast, treatment of LPS-stimulated murine bone marrow-derived DCs with 3-HAA inhibits inflammatory cytokine production (IL-12, IL-6 and TNFα), the expression of DC maturation markers (CD80, CD86 and I-A) and the capacity of DCs to stimulate Tcells [254]. Moreover, in vivo administration of 3-HAA also inhibits the ability of DCs to activate T-cells [254]. Notwithstanding the above, Ido1 gene-knockout mice do not exhibit altered DC responses towards LPS or Leishmania major infection in vivo, being both phenotypically and functionally comparable with DCs from wild-type mice [253], suggesting a certain level of redundancy in IDO1 function with respect to DC responses in mice.…”

Section: Lymphocytesmentioning

confidence: 94%

“…For example, the redox-active Kyn metabolites 3-HAA and 3-HK contribute to LPS-mediated maturation of human monocyte-derived DCs (as determined by CD80, CD86 and CD83 expression), apparently via ROS production and NF-κB activation [249]. In contrast, treatment of LPS-stimulated murine bone marrow-derived DCs with 3-HAA inhibits inflammatory cytokine production (IL-12, IL-6 and TNFα), the expression of DC maturation markers (CD80, CD86 and I-A) and the capacity of DCs to stimulate Tcells [254]. Moreover, in vivo administration of 3-HAA also inhibits the ability of DCs to activate T-cells [254].…”

Section: Lymphocytesmentioning

confidence: 99%

Role of indoleamine 2,3-dioxygenase in health and disease

et al. 2015

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IDO1 (indoleamine 2,3-dioxygenase 1) is a member of a unique class of mammalian haem dioxygenases that catalyse the oxidative catabolism of the least-abundant essential amino acid, L-Trp (L-tryptophan), along the kynurenine pathway. Significant increases in knowledge have been recently gained with respect to understanding the fundamental biochemistry of IDO1 including its catalytic reaction mechanism, the scope of enzyme reactions it catalyses, the biochemical mechanisms controlling IDO1 expression and enzyme activity, and the discovery of enzyme inhibitors. Major advances in understanding the roles of IDO1 in physiology and disease have also been realised. IDO1 is recognised as a prominent immune regulatory enzyme capable of modulating immune cell activation status and phenotype via several molecular mechanisms including enzyme-dependent deprivation of L-Trp and its conversion into the aryl hydrocarbon receptor ligand kynurenine and other bioactive kynurenine pathway metabolites, or non-enzymatic cell signalling actions involving tyrosine phosphorylation of IDO1. Through these different modes of biochemical signalling, IDO1 regulates certain physiological functions (e.g. pregnancy) and modulates the pathogenesis and severity of diverse conditions including chronic inflammation, infectious disease, allergic and autoimmune disorders, transplantation, neuropathology and cancer. In the present review, we detail the current understanding of IDO1's catalytic actions and the biochemical mechanisms regulating IDO1 expression and activity. We also discuss the biological functions of IDO1 with a focus on the enzyme's immune-modulatory function, its medical implications in diverse pathological settings and its utility as a therapeutic target.

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“…Hydroxykynurenine does display an effect which, however, is weaker than kynurenine (86). On the other hand, 3-HAA has been suggested to prime DC for expressing reduced levels of pro-inflammatory cytokines, enhanced levels of TGF-β, and inducing T reg cells (90, 91). The depletion of Trp also triggers amino-acid-sensing signal transduction pathways, such as the GCN2 kinase and inhibition of mTOR (92).…”

Section: Role Of Trp Degradationmentioning

confidence: 99%

The Role of Placental Tryptophan Catabolism

2014

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This review discusses the mechanisms and consequences of degradation of tryptophan (Trp) in the placenta, focusing mainly on the role of indoleamine 2,3-dioxygenase-1 (IDO1), one of three enzymes catalyzing the first step of the kynurenine pathway of Trp degradation. IDO1 has been implicated in regulation of feto-maternal tolerance in the mouse. Local depletion of Trp and/or the presence of metabolites of the kynurenine pathway mediate immunoregulation and exert antimicrobial functions. In addition to the decidual glandular epithelium, IDO1 is localized in the vascular endothelium of the villous chorion and also in the endothelium of spiral arteries of the decidua. Possible consequences of IDO1-mediated catabolism of Trp in the endothelium encompass antimicrobial activity and immunosuppression, as well as relaxation of the placental vasotonus, thereby contributing to placental perfusion and growth of both placenta and fetus. It remains to be evaluated whether other enzymes mediating Trp oxidation, such as indoleamine 2,3-dioxygenase-2, Trp 2,3-dioxygenase, and Trp hydroxylase-1 are of relevance to the biology of the placenta.

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The tryptophan metabolite 3-hydroxyanthranilic acid suppresses T cell responses by inhibiting dendritic cell activation

Cited by 46 publications

References 35 publications

Human Bone Marrow-Derived Mesenchymal Stromal Cells Differentially Inhibit Cytokine Production by Peripheral Blood Monocytes Subpopulations and Myeloid Dendritic Cells

Human Bone Marrow-Derived Mesenchymal Stromal Cells Differentially Inhibit Cytokine Production by Peripheral Blood Monocytes Subpopulations and Myeloid Dendritic Cells

Role of indoleamine 2,3-dioxygenase in health and disease

The Role of Placental Tryptophan Catabolism

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