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Characterization of the Kynurenine Pathway in CD8+ Human Primary Monocyte-Derived Dendritic Cells

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Abstract

The kynurenine (KYN) pathway (KP) is a major degradative pathway of the amino acid, l-tryptophan (TRP), that ultimately leads to the anabolism of the essential pyridine nucleotide, nicotinamide adenine dinucleotide. TRP catabolism results in the production of several important metabolites, including the major immune tolerance-inducing metabolite KYN, and the neurotoxin and excitotoxin quinolinic acid. Dendritic cells (DCs) have been shown to mediate immunoregulatory roles that mediated by TRP catabolism. However, characterization of the KP in human DCs has so far only been partly delineated. It is critical to understand which KP enzymes are expressed and which KP metabolites are produced to be able to understand their regulatory effects on the immune response. In this study, we characterized the KP in human monocyte-derived DCs (MDDCs) in comparison with the human primary macrophages using RT-PCR, high-pressure gas chromatography, mass spectrometry, and immunocytochemistry. Our results show that the KP is entirely expressed in human MDDC. Following activation of the KP using interferon gamma, MDDCs can mediate apoptosis of T h cells in vitro. Understanding the molecular mechanisms regulating KP metabolism in MDDCs may provide renewed insight for the development of novel therapeutics aimed at modulating immunological effects and peripheral tolerance.

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Abbreviations

QUIN:

Quinolinic acid

KP:

Kynurenine pathway

IDO:

Indoleamine 2,3-dioxygenase

TDO:

Tryptophan 2,3-dioxygenase

3-HAA:

3-Hydroxyanthranilic acid

3-HAO:

3-Hydroxyanthranilate dioxygenase

QPRTase:

Quinolinate phosphoribosyltransferase

KYN:

Kynurenine

KYNA:

Kynurenic acid

3-HK:

3-Hydroxykynurenine

PIC:

Picolinic acid

KYNase:

Kynurenase

KAT:

Kynurenine amino transferase

KMO:

Kynurenine e hydroxylase

GC–MS:

Gas chromatography–mass spectrometry

MDDC:

Monocyte-derived dendritic cells

MdM:

Blood monocyte-derived macrophages

ACMSDase:

Picolinic carboxylase

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Acknowledgments

The National Health and Medical Research Council (Fellowship and Program Grant), the NSW Health Department, the University of New South Wales, the Rebecca L. Cooper Medical Foundation and Private Donation from M. Terry Gammel have supported this work. NB is the recipient of an Alzheimer’s Australia Viertel Foundation Postdoctoral Research Fellowship and the NHMRC Early Career Researcher Postdoctoral Fellowship at the University of New South Wales.

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Authors and Affiliations

  1. Centre for Healthy Brain Ageing, School of Psychiatry, Faculty of Medicine, University of New South Wales, Sydney, Australia

    Nady Braidy

  2. St Vincent’s Centre for Applied Medical Research, Sydney, Australia

    Helene Rossez & Bruce J. Brew

  3. Neuropharmacology Group, MND and Neurodegenerative Diseases Research Centre, Macquarie University, Sydney, NSW, 2109, Australia

    Chai K. Lim & Gilles J. Guillemin

  4. School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, Australia

    Bat-Erdene Jugder

  5. Department of Neurology and HIV Medicine, St Vincent’s Hospital, Sydney, Australia

    Bruce J. Brew

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  1. Nady Braidy
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  2. Helene Rossez
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  3. Chai K. Lim
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  4. Bat-Erdene Jugder
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  5. Bruce J. Brew
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  6. Gilles J. Guillemin
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Correspondence to Nady Braidy or Gilles J. Guillemin.

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Braidy, N., Rossez, H., Lim, C.K. et al. Characterization of the Kynurenine Pathway in CD8+ Human Primary Monocyte-Derived Dendritic Cells. Neurotox Res 30, 620–632 (2016). https://doi.org/10.1007/s12640-016-9657-x

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  • DOI: https://doi.org/10.1007/s12640-016-9657-x

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