| The tryptophan metabolite 3-hydroxyanthranilic acid plays anti-inflammatory and neuroprotective roles during inflammation: role of hemeoxygenase-1. | |
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MedLine Citation:
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PMID: 21855684 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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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 |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: The American journal of pathology Volume: 179 ISSN: 1525-2191 ISO Abbreviation: Am. J. Pathol. Publication Date: 2011 Sep |
Date Detail:
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Created Date: 2011-08-22 Completed Date: 2011-12-09 Revised Date: 2012-02-22 |
Medline Journal Info:
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Nlm Unique ID: 0370502 Medline TA: Am J Pathol Country: United States |
Other Details:
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Languages: eng Pagination: 1360-72 Citation Subset: AIM; IM |
Copyright Information:
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Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. |
Affiliation:
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Department of Pathology (Neuropathology), Albert Einstein College of Medicine, Bronx, New York, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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3-Hydroxyanthranilic Acid
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metabolism,
pharmacology* Adult Animals Anti-Inflammatory Agents / pharmacology* Astrocytes / metabolism Cell Death / drug effects Cells, Cultured Chemokines / metabolism Cytokines / metabolism Heme Oxygenase-1 / metabolism* Humans Interferon-gamma / pharmacology Interleukin-1 / pharmacology Kynurenine / analogs & derivatives, metabolism Mice Microglia / metabolism Neurons / drug effects Nootropic Agents / pharmacology* |
| Grant Support | |
ID/Acronym/Agency:
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K01 MH084705/MH/NIMH NIH HHS; P30 AI051519/AI/NIAID NIH HHS; R01 MH55477/MH/NIMH NIH HHS; R25 MH080663-05/MH/NIMH NIH HHS; T32 NS007098/NS/NINDS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Anti-Inflammatory Agents; 0/Chemokines; 0/Cytokines; 0/Interleukin-1; 0/Nootropic Agents; 343-65-7/Kynurenine; 484-78-6/3-hydroxykynurenine; 548-93-6/3-Hydroxyanthranilic Acid; 82115-62-6/Interferon-gamma; EC 1.14.99.3/Heme Oxygenase-1 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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