| Xanthine oxidoreductase promotes the inflammatory state of mononuclear phagocytes through effects on chemokine expression, peroxisome proliferator-activated receptor-{gamma} sumoylation, and HIF-1{alpha}. | |
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MedLine Citation:
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PMID: 21059659 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The protective effects of pharmacological inhibitors of xanthine oxidoreductase (XOR) have implicated XOR in many inflammatory diseases. Nonetheless, the role played by XOR during inflammation is poorly understood. We previously observed that inhibition of XOR within the inflammatory mononuclear phagocytes (MNP) prevented neutrophil recruitment during adoptive transfer demonstrating the role of XOR in MNP-mediated neutrophil recruitment. To further explore the role of XOR in the inflammatory state of MNP, we studied MNP isolated from inflammatory lungs combined with analyses of MNP cell lines. We demonstrated that XOR activity was increased in inflammatory MNP following insufflation of Th-1 cytokines in vivo and that activity was specifically increased by MNP differentiation. Inhibition of XOR reduced levels of CINC-1 secreted by MNP. Expression of peroxisome proliferator-activated receptor γ (PPARγ) in purified rat lung MNP and MNP cell lines reflected both the presence of PPARγ isoforms and PPARγ SUMOylation, and XOR inhibitors increased levels of SUMO-PPARγ in MNP cell lines. Both ectopic overexpression of XOR cDNA and uric acid supplementation reduced SUMO-PPARγ in MNP cells. Levels of the M2 markers CD36, CD206, and arginase-1 were modulated by uric acid and oxonic acid, whereas siRNA to SUMO-1 or PIAS-1 also reduced arginase-1 in RAW264.7 cells. We also observed that HIF-1α was increased by XOR inhibitors in inflammatory MNP and in MNP cell lines. These data demonstrate that XOR promotes the inflammatory state of MNP through effects on chemokine expression, PPARγ SUMOylation, and HIF-1α and suggest that strategies for inhibiting XOR may be valuable in modulating lung inflammatory disorders. |
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Authors:
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Sophie Gibbings; Nancy D Elkins; Hillary Fitzgerald; Janice Tiao; Mari E Weyman; Gayle Shibao; Mehdi A Fini; Richard M Wright |
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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 Date: 2010-11-08 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 286 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2011 Jan |
Date Detail:
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Created Date: 2011-01-10 Completed Date: 2011-03-02 Revised Date: 2012-01-16 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 961-75 Citation Subset: IM |
Affiliation:
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Division of Pulmonary Sciences, Division of Pulmonary Sciences, University of Colorado Denver, Aurora, Colorado 80045, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cell Differentiation / immunology Chemokine CXCL1 / metabolism Chemokines / metabolism* Enzyme Activation / immunology HL-60 Cells Humans Hypoxia-Inducible Factor 1, alpha Subunit / metabolism* Male Neutrophils / immunology PPAR gamma / metabolism* Phagocytes / cytology, enzymology, immunology* Pneumonia / immunology*, metabolism Rats Rats, Sprague-Dawley Sumoylation / immunology Th1 Cells / cytology, enzymology, immunology U937 Cells Uric Acid / metabolism Xanthine Dehydrogenase / antagonists & inhibitors, immunology*, metabolism |
| Grant Support | |
ID/Acronym/Agency:
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HL-45582/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Chemokine CXCL1; 0/Chemokines; 0/Cxcl1 protein, rat; 0/HIF1A protein, human; 0/Hif1a protein, rat; 0/Hypoxia-Inducible Factor 1, alpha Subunit; 0/PPAR gamma; 69-93-2/Uric Acid; EC 1.17.1.4/Xanthine Dehydrogenase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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