The tryptophan metabolite 3-hydroxyanthranilic acid plays anti-inflammatory and neuroprotective roles during inflammation: Role of hemeoxygenase-1

Daniela Krause, Hyeon Sook Suh, Leonid Tarassishin, Qiao Ling Cui, Bryce A. Durafourt, Namjong Choi, Avital Bauman, Melissa Cosenza-Nashat, Jack P. Antel, Meng Liang Zhao, Sunhee C. Lee

Research output: Contribution to journalArticle

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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 radicalgenerating 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-HAAmediated 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.

Original languageEnglish (US)
Pages (from-to)1360-1372
Number of pages13
JournalAmerican Journal of Pathology
Volume179
Issue number3
DOIs
StatePublished - Sep 2011

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3-Hydroxyanthranilic Acid
Heme Oxygenase-1
Tryptophan
Anti-Inflammatory Agents
Inflammation
Cytokines
Kynurenine
Microglia
Astrocytes
Central Nervous System
Antioxidants
Quinolinic Acid
Toll-Like Receptors
Interleukin-1
Chemokines
Neuroglia
Interferons
Communicable Diseases
Lipopolysaccharides
Western Blotting

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

The tryptophan metabolite 3-hydroxyanthranilic acid plays anti-inflammatory and neuroprotective roles during inflammation : Role of hemeoxygenase-1. / Krause, Daniela; Suh, Hyeon Sook; Tarassishin, Leonid; Cui, Qiao Ling; Durafourt, Bryce A.; Choi, Namjong; Bauman, Avital; Cosenza-Nashat, Melissa; Antel, Jack P.; Zhao, Meng Liang; Lee, Sunhee C.

In: American Journal of Pathology, Vol. 179, No. 3, 09.2011, p. 1360-1372.

Research output: Contribution to journalArticle

Krause, D, Suh, HS, Tarassishin, L, Cui, QL, Durafourt, BA, Choi, N, Bauman, A, Cosenza-Nashat, M, Antel, JP, Zhao, ML & Lee, SC 2011, 'The tryptophan metabolite 3-hydroxyanthranilic acid plays anti-inflammatory and neuroprotective roles during inflammation: Role of hemeoxygenase-1', American Journal of Pathology, vol. 179, no. 3, pp. 1360-1372. https://doi.org/10.1016/j.ajpath.2011.05.048
Krause, Daniela ; Suh, Hyeon Sook ; Tarassishin, Leonid ; Cui, Qiao Ling ; Durafourt, Bryce A. ; Choi, Namjong ; Bauman, Avital ; Cosenza-Nashat, Melissa ; Antel, Jack P. ; Zhao, Meng Liang ; Lee, Sunhee C. / The tryptophan metabolite 3-hydroxyanthranilic acid plays anti-inflammatory and neuroprotective roles during inflammation : Role of hemeoxygenase-1. In: American Journal of Pathology. 2011 ; Vol. 179, No. 3. pp. 1360-1372.
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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 radicalgenerating 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-HAAmediated 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.",
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