| Redox modification of cysteine residues regulates the cytokine activity of HMGB1. | |
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MedLine Citation:
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PMID: 22105604 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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High mobility group box 1 (HMGB1) is a nuclear protein with extracellular inflammatory cytokine activity. It is passively released during cell injury and necrosis, and actively secreted by immune cells. HMGB1 contains three conserved redox-sensitive cysteine residues: C23 and C45 can form an intra-molecular disulfide bond, whereas C106 is unpaired and is essential for the interaction with Toll-Like Receptor (TLR) 4. However, a comprehensive characterization of the dynamic redox states of each cysteine residue and of their impacts on innate immune responses is lacking. Using tandem mass-spectrometric analysis we have now established that the C106 thiol and the C23-C45 disulfide bond are required for HMGB1 to induce nuclear NF-kB translocation and TNF production in macrophages. Both irreversible oxidation to sulphonates and complete reduction to thiols of these cysteines markedly inhibited TNF production. In a proof of concept murine model of hepatic necrosis induced by acetaminophen, during inflammation the predominant form of serum HMGB1 is the active one, containing a C106 thiol group and a disulfide bond between C23-C45, whereas the inactive form of HMGB1, containing terminally oxidized cysteines, accumulates during inflammation resolution and hepatic regeneration. These results reveal critical post-translational redox mechanisms that control the pro-inflammatory activity of HMGB1 and its inactivation during pathogenesis. |
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Authors:
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Huan Yang; Peter Lundbäck; Lars Ottosson; Helena Erlandsson-Harris; Emilie Venereau; Marco E Bianchi; Yousef Al-Abed; Ulf Andersson; Kevin J Tracey; Daniel J Antoine |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-11-07 |
Journal Detail:
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Title: Molecular medicine (Cambridge, Mass.) Volume: - ISSN: 1528-3658 ISO Abbreviation: - Publication Date: 2011 Nov |
Date Detail:
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Created Date: 2011-11-22 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9501023 Medline TA: Mol Med Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030, USA. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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