Abstract
3-Hydroxyanthranilic acid (HAA), a compound generated during tryptophan metabolism initiated by indoleamine 2,3-dioxygenase, is known to induce T cell death, but its molecular target is not known. Here we report that HAA inhibits NF-kappaB activation upon T cell antigen receptor engagement by specifically targeting PDK1. Inhibition of NF-kappaB by HAA leads to dysfunction and cell death of activated Th2 cells, which in turn suppresses experimental asthma. Inhibition of NF-kappaB and induction of apoptosis is specific to CD4 T cells because HAA does not inhibit NF-kappaB activation or induce cell death upon Toll-like receptor 4 stimulation in dendritic cells. Thus, HAA is a natural inhibitor that restrains T cell expansion and activation.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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3-Hydroxyanthranilic Acid / pharmacology*
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Animals
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Apoptosis / drug effects
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Asthma / chemically induced
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Asthma / immunology*
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Asthma / prevention & control*
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Cell Line
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Disease Models, Animal
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Enzyme Activation / drug effects
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Humans
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Lymphocyte Activation / drug effects
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Mice
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Models, Molecular
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NF-kappa B / metabolism
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Phosphorylation / drug effects
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Protein Serine-Threonine Kinases / chemistry
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Protein Serine-Threonine Kinases / metabolism*
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Protein Structure, Tertiary
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Pyruvate Dehydrogenase Acetyl-Transferring Kinase
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Receptors, Antigen, T-Cell / immunology
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Receptors, Antigen, T-Cell / metabolism
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T-Lymphocytes / cytology
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T-Lymphocytes / drug effects*
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T-Lymphocytes / enzymology*
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T-Lymphocytes / immunology
Substances
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NF-kappa B
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PDK1 protein, human
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Pdk1 protein, mouse
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Pyruvate Dehydrogenase Acetyl-Transferring Kinase
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Receptors, Antigen, T-Cell
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3-Hydroxyanthranilic Acid
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Protein Serine-Threonine Kinases