Abstract
Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-catabolizing enzyme that, expressed by different cell types, has regulatory effects on T cells resulting from tryptophan depletion in specific local tissue microenvironments. Different mechanisms, however, might contribute to IDO-dependent immune regulation. We show here that tryptophan metabolites in the kynurenine pathway, such as 3-hydroxyanthranilic and quinolinic acids, will induce the selective apoptosis in vitro of murine thymocytes and of Th1 but not Th2 cells. T cell apoptosis was observed at relatively low concentrations of kynurenines, did not require Fas/Fas ligand interactions, and was associated with the activation of caspase-8 and the release of cytochrome c from mitochondria. When administered in vivo, the two kynurenines caused depletion of specific thymocyte subsets in a fashion qualitatively similar to dexamethasone. These data suggest that the selective deletion of T lymphocytes may be a major mechanism whereby tryptophan metabolism affects immunity under physiopathologic conditions.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3-Hydroxyanthranilic Acid / metabolism
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3-Hydroxyanthranilic Acid / pharmacology
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Animals
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Apoptosis / drug effects
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Apoptosis / physiology*
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Autoimmune Diseases / immunology*
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Caspase 8
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Caspase 9
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Caspase Inhibitors
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Caspases / metabolism
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Cell Nucleus / drug effects
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Cell Nucleus / metabolism
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Cell Nucleus / ultrastructure
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Cells, Cultured
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Cytochrome c Group / drug effects
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Cytochrome c Group / metabolism
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Cytosol / drug effects
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Cytosol / metabolism
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Dose-Response Relationship, Drug
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Kynurenine / metabolism*
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Mice
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Mice, Inbred C57BL
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Mice, Inbred DBA
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Microscopy, Electron
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Mitochondria / drug effects
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Mitochondria / metabolism
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Quinolinic Acid / metabolism
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Quinolinic Acid / pharmacology
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Self Tolerance / immunology*
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T-Lymphocytes / drug effects
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T-Lymphocytes / metabolism*
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T-Lymphocytes / ultrastructure
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Th1 Cells / drug effects
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Th1 Cells / metabolism
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Th1 Cells / ultrastructure
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Thymus Gland / drug effects
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Thymus Gland / metabolism
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Thymus Gland / ultrastructure
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Tryptophan / metabolism*
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fas Receptor / genetics
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fas Receptor / metabolism
Substances
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Caspase Inhibitors
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Cytochrome c Group
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fas Receptor
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3-Hydroxyanthranilic Acid
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Kynurenine
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Tryptophan
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Casp8 protein, mouse
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Casp9 protein, mouse
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Caspase 8
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Caspase 9
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Caspases
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Quinolinic Acid