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The Journal of Neuroscience, November 21, 2007, 27(47):12884-12892; doi:10.1523/JNEUROSCI.4101-07.2007

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Neurobiology of Disease
Characterization of the Kynurenine Pathway in Human Neurons

Gilles J. Guillemin,^1,4 Karen M. Cullen,³ Chai K. Lim,⁴ George A. Smythe,² Brett Garner,⁶ Vimal Kapoor,⁷ Osamu Takikawa,⁸ and Bruce J. Brew^4,5

¹Department of Pharmacology, School of Medical Sciences, and ²Biomedical Mass Spectrometry Facility, University of New South Wales, Sydney 2052, Australia, ³Anatomy and Histology, School of Medical Science and the Bosch Institute, The University of Sydney, New South Wales 2006, Australia, ⁴Centre for Immunology and ⁵Departments of Neurology and HIV Medicine, St. Vincent's Hospital, Sydney 2010, Australia, ⁶Prince of Wales Medical Research Institute, Randwick 2031, New South Wales, Australia, ⁷Department of Medicine and Pharmacology, The University of Western Australia, Crawley 6009, Australia, and ⁸Laboratory of Radiation Safety, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, Gengo, Morioka, Obu 474-8511, Japan

Correspondence should be addressed to Dr. Gilles J. Guillemin, University of New South Wales, Wallace Wurth Building, Room 309, Sydney, NSW 2052, Australia. Email: g.guillemin{at}cfi.unsw.edu.au

The kynurenine pathway is a major route of L-tryptophan catabolism producing neuroactive metabolites implicated in neurodegeneration and immune tolerance. We characterized the kynurenine pathway in human neurons and the human SK-N-SH neuroblastoma cell line and found that the kynurenine pathway enzymes were variably expressed. Picolinic carboxylase was expressed only in primary and some adult neurons but not in SK-N-SH cells. Because of this difference, SK-N-SH cells were able to produce the excitotoxin quinolinic acid, whereas human neurons produced the neuroprotectant picolinic acid. The net result of kynurenine pathway induction in human neurons is therefore predicted to result in neuroprotection, immune regulation, and tumor inhibition, whereas in SK-N-SH cells, it may result in neurotoxicity, immune tolerance, and tumor promotion. This study represents the first comprehensive characterization of the kynurenine pathway in neurons and the first description of the involvement of the kynurenine pathway as a mechanism for controlling both tumor cell neurotoxicity and persistence.

Key words: human neurons; neuroblastoma; kynurenine pathway; indoleamine 2,3-dioxygenase; picolinic acid; quinolinic acid; neurotoxicity; tumor tolerance

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Received April 17, 2007; accepted Oct. 8, 2007.

Correspondence should be addressed to Dr. Gilles J. Guillemin, University of New South Wales, Wallace Wurth Building, Room 309, Sydney, NSW 2052, Australia. Email: g.guillemin{at}cfi.unsw.edu.au

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