1-Methyl-tryptophan can interfere with TLR signaling in dendritic cells independently of IDO activity.

Institut National de la Santé et de la Recherche Médicale Unité 503, Institut Fédératif de Recherche 128 BioSciences Lyon-Gerland, Université Claude Bernard Lyon I, 21 Avenue Tony Garnier, F-69365 Lyon, France.
The Journal of Immunology (Impact Factor: 5.36). 09/2006; 177(4):2061-71. DOI: 10.4049/jimmunol.177.4.2061
Source: PubMed

ABSTRACT The compound 1-methyl-tryptophan (1-MT) is a competitive inhibitor of IDO that can break tolerance and induce fetus, graft, and tumor rejection. Because of its broad effect on immune-related mechanisms, the direct action of 1-MT on human monocyte-derived dendritic cells (DC) was analyzed. It is shown here that the effect of 1-MT on DC is dependent on the maturation pathway. Although 1-MT had no effect on DC stimulated by the TLR3 ligand poly(I:C), it strongly enhanced the Th1 profile of DC stimulated with TLR2/1 or TLR2/6 ligands. Drastic changes in the function of DC stimulated by the TLR4 ligand LPS were induced by 1-MT. These cells could still activate allogeneic and syngeneic T cells but stimulation yielded T cells secreting IL-5 and IL-13 rather than IFN-gamma. This action of 1-MT correlated with an increased phosphorylation of p38 and ERK MAPKs and sustained activation of the transcription factor c-Fos. Inhibiting p38 and ERK phosphorylation with synthetic inhibitors blocked the effect of 1-MT on LPS-stimulated DC. Thus, 1-MT can modulate DC function depending on the maturation signal and independently of its action on IDO. This is consistent with previous observations and will help further understanding the mechanisms of DC polarization.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Mice infected with mouse hepatitis virus A59 (MHV-A59) develop autoantibodies (autoAb) to liver and kidney fumarylacetoacetate hydrolase (FAH) with a concomitant enhancement of transaminases and release of alarmins such as uric acid and high-mobility group box protein 1 (HMGB1). Tryptophan catabolism is an endogenous mechanism that restricts excessive immune responses, thereby preventing immunopathology. Since indoleamine-2,3-dioxygenase (IDO) is the key and rate-limiting enzyme of tryptophan catabolism, the aim of this work was to explore whether specific inhibition of IDO by Levo-1-methyl tryptophan (MT) could affect MHV actions. Results showed that MT strongly enhanced the hypergammaglobulinemia induced by the virus, as well as anti-MHV Ab and uric acid release. Moreover, infected mice treated with MT did express anti-FAH autoAb and high levels of serum HMGB1. Survival of MHV-infected animals treated with MT was severely reduced compared with that of MHV-infected mice or controls only treated with MT. Furthermore, histological liver examination indicated that MT induced fibrosis in MHV-infected animals, whereas MT itself increased uric acid levels without shortening the animal life Thus, under our experimental conditions, results indicated an exacerbated response to MHV infection when IDO was blocked by MT. Copyright © 2014. Published by Elsevier B.V.
    International immunopharmacology. 01/2015;
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The kynurenine pathway (KP) metabolizes the essential amino acid tryptophan and generates a number of neuroactive metabolites collectively called the kynurenines. Segregated into at least two distinct branches, often termed the "neurotoxic" and "neuroprotective" arms of the KP, they are regulated by the two enzymes kynurenine 3-monooxygenase and kynurenine aminotransferase, respectively. Interestingly, several enzymes in the pathway are under tight control of inflammatory mediators. Recent years have seen a tremendous increase in our understanding of neuroinflammation in CNS disease. This review will focus on the regulation of the KP by inflammatory mediators as it pertains to neurodegenerative and psychiatric disorders.
    Frontiers in Neuroscience 01/2014; 8:12.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mesenchymal stromal cells (MSCs) exhibit the inherent potential to regulate multiple signaling pathways and cell types that contribute to the pathogenesis of inflammatory and immune diseases. However, more recent studies have suggested that the secretion of immunomodulatory factors by MSCs can be enhanced by three-dimensional aggregation or pro-inflammatory cytokine treatment. Human MSC spheroids were formed by forced aggregation into agarose micro-wells and subsequently cultured in either minimal essential medium alpha supplemented with fetal bovine serum or serum-free, defined MesenCult-XF medium (STEMCELL Technologies, Vancouver, Canada). A subset of the spheroids were treated with pro-inflammatory cytokines interferon (IFN)-γ or tumor necrosis factor (TNF)-α or both for 4 days. Immunomodulatory factor (prostaglandin E2, indoleamine 2,3-dioxygenase, transforming growth factor-β1 and interleukin-6) secretion was quantified after 4 days of culture, and the immunomodulatory activity of MSCs was assessed by quantifying activated macrophage expression of TNF-α after trans-well co-culture. Culturing human MSCs as three-dimensional aggregates increased secretion of immunomodulatory paracrine factors, which was enhanced further by treatment with IFN-γ and TNF-α, demonstrating that these parameters can synergistically enhance endogenous human MSC immunomodulatory properties. However, immunomodulatory factor secretion was found to be highly dependent on the composition of cell culture medium. Human MSCs cultured in MesenCult-XF medium displayed significantly less expression of prostaglandin E2, indoleamine 2,3-dioxygenase, transforming growth factor-β1 and interleukin-6 compared with human MSCs cultured in medium supplemented with fetal bovine serum. Finally, pre-conditioning of human MSC spheroids with IFN-γ and TNF-α resulted in greater immunomodulatory activity in a macrophage co-culture assay. Altogether, engineering the environment of human MSCs to develop pre-conditioning strategies for enhancing human MSC immunomodulation may be a simple approach for improving MSC-based therapies for the treatment of inflammatory and immune diseases.
    Cytotherapy 11/2013; · 3.06 Impact Factor


Available from
Jun 1, 2014