3-Hydroxyanthranilic acid inhibits PDK1 activation and suppresses experimental asthma by inducing T cell apoptosis.
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.
Hayashi
Tomoko
T
Department of Medicine, University of California at San Diego, La Jolla, CA 92093-0663, USA.
Mo
Ji-Hun
JH
Gong
Xing
X
Rossetto
Cyprian
C
Jang
Angela
A
Beck
Lucinda
L
Elliott
Gregory I
GI
Kufareva
Irina
I
Abagyan
Ruben
R
Broide
David H
DH
Lee
Jongdae
J
Raz
Eyal
E
D015095:3-Hydroxyanthranilic Acid / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001249:Asthma / Q000139:chemically induced / Q000276:immunology* / Q000517:prevention & control*; D002460:Cell Line; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008958:Models, Molecular; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology* / Q000276:immunology
D016328:NF-kappa B; C000631429:PDK1 protein, human; C000631433:Pdk1 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011948:Receptors, Antigen, T-Cell; D015095:3-Hydroxyanthranilic Acid; D017346:Protein Serine-Threonine Kinases