Journal Article

3-Hydroxyanthranilic acid inhibits PDK1 activation and suppresses experimental asthma by inducing T cell apoptosis

Gong, Xing, Raz, Eyal, Beck, Lucinda, Kufareva, Irina, Lee, Jongdae, Elliott, Gregory I, Jang, Angela, Hayashi, Tomoko, Broide, David H, Mo, Ji-Hun, Rossetto, Cyprian, Abagyan, Ruben

2007

Overview

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-κB activation upon T cell antigen receptor engagement by specifically targeting PDK1. Inhibition of NF-κB by HAA leads to dysfunction and cell death of activated Th2 cells, which in turn suppresses experimental asthma. Inhibition of NF-κB and induction of apoptosis is specific to CD4 T cells because HAA does not inhibit NF-κB 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.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: 3-Hydroxyanthranilic Acid - pharmacology / Acids / Animals / antigens / Apoptosis / Apoptosis - drug effects / Asthma / Asthma - chemically induced / Asthma - immunology / Asthma - prevention & control / Biological Sciences / CD4-positive T-lymphocytes / Cell death / Cell Line / Cytokines / dendritic cells / Disease Models, Animal / Enzyme Activation - drug effects / Humans / indoleamine 2,3-dioxygenase / Lungs / Lymphocyte Activation - drug effects / Metabolism / Mice / Models, Molecular / Molecules / Mortality / NF-kappa B - metabolism / Ova / Phosphorylation / Phosphorylation - drug effects / Protein Structure, Tertiary / Protein-Serine-Threonine Kinases - antagonists & inhibitors / Protein-Serine-Threonine Kinases - chemistry / Protein-Serine-Threonine Kinases - metabolism / Receptors, Antigen, T-Cell - immunology / Receptors, Antigen, T-Cell - metabolism / T cell antigen receptors / T cell receptors / T lymphocytes / T-Lymphocytes - cytology / T-Lymphocytes - drug effects / T-Lymphocytes - enzymology / T-Lymphocytes - immunology / Toll-like receptor 4 / transcription factor NF-kappa B / tryptophan