title: The tryptophan metabolite 3-hydroxyanthranilic acid plays anti-inflammatory and neuroprotective roles during inflammation: role of hemeoxygenase-1.
abstract: Tryptophan metabolism by the kynurenine pathway (KP) is important to the pathogenesis of inflammatory, infectious, and degenerative diseases. The 3-hydroxykynurenine (3-HK) branch of the KP is activated in macrophages and microglia, leading to the generation of 3-HK, 3-hydroxyanthranilic acid (3-HAA), and quinolinic acid, which are considered neurotoxic owing to their free radical-generating and N-methyl-d-aspartic acid receptor agonist activities. We investigated the role of 3-HAA in inflammatory and antioxidant gene expression and neurotoxicity in primary human fetal central nervous system cultures treated with cytokines (IL-1 with or without interferon-γ) or with Toll-like receptor ligands mimicking the proinflammatory central nervous system environment. Results were analyzed by microarray, Western blot, immunostain, enzyme-linked immunosorbent assay, and neurotoxicity assays. 3-HAA suppressed glial cytokine and chemokine expression and reduced cytokine-induced neuronal death. 3-HK also suppressed cytokine-induced neuronal death. Unexpectedly, 3-HAA was highly effective in inducing in astrocytes the expression of hemeoxygenase-1 (HO-1), an antioxidant enzyme with anti-inflammatory and cytoprotective properties. Optimal induction of HO-1 required 3-HAA and cytokines. In human microglia, 3-HAA weakly induced HO-1 and lipopolysaccharide suppressed microglial HO-1 expression. 3-HAA-mediated HO-1 expression was confirmed in cultured adult human astrocytes and in vivo after 3-HAA injection to mouse brains. Together, our results demonstrate the novel neuroprotective activity of the tryptophan metabolite 3-HAA and have implications for future therapeutic approaches for neuroinflammatory disorders.
authors.affiliation: Department of Pathology (Neuropathology), Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Daniela
authors.initials: D
authors.lastname: Krause
authors.forename: Hyeon-Sook
authors.initials: HS
authors.lastname: Suh
authors.forename: Leonid
authors.initials: L
authors.lastname: Tarassishin
authors.forename: Qiao Ling
authors.initials: QL
authors.lastname: Cui
authors.forename: Bryce A
authors.initials: BA
authors.lastname: Durafourt
authors.forename: Namjong
authors.initials: N
authors.lastname: Choi
authors.forename: Avital
authors.initials: A
authors.lastname: Bauman
authors.forename: Melissa
authors.initials: M
authors.lastname: Cosenza-Nashat
authors.forename: Jack P
authors.initials: JP
authors.lastname: Antel
authors.forename: Meng-Liang
authors.initials: ML
authors.lastname: Zhao
authors.forename: Sunhee C
authors.initials: SC
authors.lastname: Lee
mesh_terms: D015095:3-Hydroxyanthranilic Acid / Q000378:metabolism / Q000494:pharmacology*; D000328:Adult; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001253:Astrocytes / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D007737:Kynurenine / Q000031:analogs & derivatives / Q000378:metabolism; D051379:Mice; D017628:Microglia / Q000378:metabolism; D009474:Neurons / Q000187:drug effects; D018697:Nootropic Agents / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D018925:Chemokines; D016207:Cytokines; D007375:Interleukin-1; D018697:Nootropic Agents; D015095:3-Hydroxyanthranilic Acid; C005045:3-hydroxykynurenine; D007737:Kynurenine; D007371:Interferon-gamma; D051547:Heme Oxygenase-1