3-Hydroxyanthranilic acid, one of metabolites of tryptophan via indoleamine 2,3-dioxygenase pathway, suppresses inducible nitric oxide synthase expression by enhancing heme oxygenase-1 expression.
Inducible nitric oxide (NO) synthase (iNOS), heme oxygenase (HO)-1, and indoleamine 2,3-dioxygenase (IDO) are simultaneously expressed in murine macrophages stimulated with interferon (IFN)-gamma and lipopolysaccharide (LPS). NO produced by iNOS suppresses IDO expression and also induces HO-1 expression. The antioxidant 3-hydroxyanthranilic acid (HA), one of metabolites of tryptophan via IDO pathway, has been previously reported to suppress iNOS expression. Because HO-1 expression can suppress iNOS expression, we investigated whether HA could suppress iNOS expression by affecting HO-1 expression in murine RAW 264.7 macrophages stimulated with IFN-gamma plus LPS. Treatment with exogenous HA dose-dependently suppressed iNOS expression and coincidently enhanced HO-1 expression. This suppressive effect of HA on iNOS expression was reversed by blocking HO-1 activity, and proven to be due to carbon monoxide (CO) produced by HO-1. In addition, either blocking of iNOS activity or addition of exogenous CO further enhanced IDO expression and activity. These results show for the first time that HA is able to suppress iNOS expression by enhancing HO-1 expression, thereby resulting in further increases in IDO expression and activity.
Oh
Gi-Su
GS
Genomic Research Center for Immune Disorders, Department of Microbiology and Immunology, Wonkwang University School of Medicine, Iksan, Chonbuk 570-749, Republic of Korea.
Pae
Hyun-Ock
HO
Choi
Byung-Min
BM
Chae
Soo-Cheon
SC
Lee
Ho-Sub
HS
Ryu
Do-Gon
DG
Chung
Hun-Taeg
HT
D015095:3-Hydroxyanthranilic Acid / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D051547:Heme Oxygenase-1; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D015398:Signal Transduction / Q000502:physiology; D014364:Tryptophan / Q000378:metabolism*; D014366:Tryptophan Oxygenase / Q000378:metabolism*
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D015095:3-Hydroxyanthranilic Acid; D007371:Interferon-gamma; D014364:Tryptophan; D014366:Tryptophan Oxygenase; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse