| Inflammasome-dependent release of the alarmin HMGB1 in endotoxemia. | |
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MedLine Citation:
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PMID: 20802146 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Endotoxin administration recapitulates many of the host responses to sepsis. Inhibitors of the cysteine protease caspase 1 have long been sought as a therapeutic because mice lacking caspase 1 are resistant to LPS-induced endotoxic shock. According to current thinking, caspase 1-mediated shock requires the proinflammatory caspase 1 substrates IL-1β and IL-18. We show, however, that mice lacking both IL-1β and IL-18 are normally susceptible to LPS-induced splenocyte apoptosis and endotoxic shock. This finding indicates the existence of another caspase 1-dependent mediator of endotoxemia. Reduced serum high mobility group box 1 (HMGB1) levels in caspase 1-deficient mice correlated with their resistance to LPS. A critical role for HMGB1 in endotoxemia was confirmed when mice deficient for IL-1β and IL-18 were protected from a lethal dose of LPS by pretreatment with HMGB1-neutralizing Abs. We found that HMGB1 secretion from LPS-primed macrophages required the inflammasome components apoptotic speck protein containing a caspase activation and recruitment domain (ASC), caspase 1 and Nalp3, whereas HMGB1 secretion from macrophages infected in vitro with Salmonella typhimurium was dependent on caspase 1 and Ipaf. Thus, HMGB1 secretion, which is critical for endotoxemia, occurs downstream of inflammasome assembly and caspase 1 activation. |
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Authors:
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Mohamed Lamkanfi; Anasuya Sarkar; Lieselotte Vande Walle; Alberto C Vitari; Amal O Amer; Mark D Wewers; Kevin J Tracey; Thirumala-Devi Kanneganti; Vishva M Dixit |
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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: 2010-08-27 |
Journal Detail:
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Title: Journal of immunology (Baltimore, Md. : 1950) Volume: 185 ISSN: 1550-6606 ISO Abbreviation: J. Immunol. Publication Date: 2010 Oct |
Date Detail:
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Created Date: 2010-09-22 Completed Date: 2010-10-19 Revised Date: 2012-04-16 |
Medline Journal Info:
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Nlm Unique ID: 2985117R Medline TA: J Immunol Country: United States |
Other Details:
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Languages: eng Pagination: 4385-92 Citation Subset: AIM; IM |
Affiliation:
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Department of Physiological Chemistry, Genentech, South San Francisco, CA 94080, USA. Mohamed.Lamkanfi@VIB-UGent.be |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Blotting, Western Caspase 1 / immunology, metabolism Endotoxemia / immunology, metabolism* Enzyme Activation / immunology Enzyme-Linked Immunosorbent Assay HMGB1 Protein / immunology, metabolism* Inflammation / immunology, metabolism* Macrophages / immunology, metabolism Male Mice Mice, Inbred C57BL Mice, Knockout Microscopy, Fluorescence Salmonella Infections / immunology, metabolism |
| Grant Support | |
ID/Acronym/Agency:
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AR056296/AR/NIAMS NIH HHS; R01 HL076278/HL/NHLBI NIH HHS; R01 HL094586-02/HL/NHLBI NIH HHS; R21 AI083871-01/AI/NIAID NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/HMGB1 Protein; EC 3.4.22.36/Caspase 1 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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