| Tumor necrosis factor induces GSK3 kinase-mediated cross-tolerance to endotoxin in macrophages. | |
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MedLine Citation:
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PMID: 21602809 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Endotoxin tolerance, a key mechanism for suppressing excessive inflammatory cytokine production, is induced by prior exposure of macrophages to Toll-like receptor (TLR) ligands. Induction of cross-tolerance to endotoxin by endogenous cytokines has not been investigated. Here we show that prior exposure to tumor necrosis factor (TNF) induced a tolerant state in macrophages, with less cytokine production after challenge with lipopolysaccharide (LPS) and protection from LPS-induced death. TNF-induced cross-tolerization was mediated by suppression of LPS-induced signaling and chromatin remodeling. TNF-induced cross-tolerance was dependent on the kinase GSK3, which suppressed chromatin accessibility and promoted rapid termination of signaling via the transcription factor NF-κB by augmenting negative feedback by the signaling inhibitors A20 and IκBα. Our results demonstrate an unexpected homeostatic function for TNF and a GSK3-mediated mechanism for the prevention of prolonged and excessive inflammation. |
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Authors:
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Sung Ho Park; Kyung-Hyun Park-Min; Janice Chen; Xiaoyu Hu; Lionel B Ivashkiv |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2011-05-22 |
Journal Detail:
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Title: Nature immunology Volume: 12 ISSN: 1529-2916 ISO Abbreviation: Nat. Immunol. Publication Date: 2011 Jul |
Date Detail:
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Created Date: 2011-06-20 Completed Date: 2011-08-23 Revised Date: 2012-05-10 |
Medline Journal Info:
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Nlm Unique ID: 100941354 Medline TA: Nat Immunol Country: United States |
Other Details:
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Languages: eng Pagination: 607-15 Citation Subset: IM |
Affiliation:
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Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, New York, New York, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Chromatin Assembly and Disassembly / drug effects, immunology Cysteine Endopeptidases / immunology, metabolism Cytokines / biosynthesis, immunology Endotoxins / immunology* Female Glycogen Synthase Kinase 3 / immunology* I-kappa B Proteins / immunology, metabolism Intracellular Signaling Peptides and Proteins / immunology, metabolism Lipopolysaccharides / immunology Macrophages / drug effects, immunology* Male Mice Mice, Inbred C57BL NF-kappa B / immunology, metabolism Toll-Like Receptors / immunology, metabolism Tumor Necrosis Factor-alpha / immunology* |
| Grant Support | |
ID/Acronym/Agency:
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R01 AI046712-11/AI/NIAID NIH HHS; R01 AI046712-12/AI/NIAID NIH HHS; R01 AI046712-13/AI/NIAID NIH HHS; R01 AR046713-11A1/AR/NIAMS NIH HHS; R01 AR046713-12/AR/NIAMS NIH HHS; R01 AR046713-13/AR/NIAMS NIH HHS; R01 AR050401/AR/NIAMS NIH HHS; R01 AR050401-06A2/AR/NIAMS NIH HHS; R01 AR050401-07/AR/NIAMS NIH HHS; R01 AR056729-03/AR/NIAMS NIH HHS; R01 DE019420-03/DE/NIDCR NIH HHS; R01 DE019420-04/DE/NIDCR NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Cytokines; 0/Endotoxins; 0/I-kappa B Proteins; 0/Intracellular Signaling Peptides and Proteins; 0/Lipopolysaccharides; 0/NF-kappa B; 0/Toll-Like Receptors; 0/Tumor Necrosis Factor-alpha; 139874-52-5/NF-kappaB inhibitor alpha; EC 2.7.11.26/Glycogen Synthase Kinase 3; EC 3.4.22.-/Cysteine Endopeptidases; EC 3.4.22.-/Tnfaip3 protein, mouse |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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