Tolerization with BLP down-regulates HMGB1 a critical mediator of sepsis-related lethality.
Authors
Coffey, J CalvinWang, Jiang Huai
Kelly, Ray
Romics, Laszlo Jr
O'Callaghan, Adrian
Fiuza, Carmen
Redmond, H Paul
Affiliation
Department of Academic Surgery, University College Cork (UCC)/National University, of Ireland (NUI), Cork University Hospital, Cork, Ireland.Issue Date
2012-02-03T15:16:48ZMeSH
AnimalsAntibodies/pharmacology
Bacterial Proteins/*toxicity
Cell Line
Down-Regulation/drug effects/immunology
HMGB1 Protein/biosynthesis/*immunology
Humans
*Immune Tolerance/drug effects
Lipoproteins/*toxicity
Macrophages, Peritoneal/*immunology/metabolism/pathology
Male
Mice
Sepsis/chemically induced/*immunology/metabolism/prevention & control
Transcription, Genetic/drug effects/immunology
Metadata
Show full item recordCitation
J Leukoc Biol. 2007 Oct;82(4):906-14. Epub 2007 Jul 11.Journal
Journal of leukocyte biologyDOI
10.1189/jlb.0806504PubMed ID
17626148Abstract
Tolerization with bacterial lipoprotein (BLP) affords a significant survival benefit in sepsis. Given that high mobility group box protein-1 (HMGB1) is a recognized mediator of sepsis-related lethality, we determined if tolerization with BLP leads to alterations in HMGB1. In vitro, BLP tolerization led to a reduction in HMGB1 gene transcription. This was mirrored at the protein level, as HMGB1 protein expression and release were reduced significantly in BLP-tolerized human THP-1 monocytic cells. BLP tolerance in vivo led to a highly significant, long-term survival benefit following challenge with lethal dose BLP in C57BL/6 mice. This was associated with an attenuation of HMGB1 release into the circulation, as evidenced by negligible serum HMGB1 levels in BLP-tolerized mice. Moreover, HMGB1 levels in peritoneal macrophages from BLP-tolerized mice were reduced significantly. Hence, tolerization with BLP leads to a down-regulation of HMGB1 protein synthesis and release. The improved survival associated with BLP tolerance could thus be explained by a reduction in HMGB1, were the latter associated with lethality in BLP-related sepsis. In testing this hypothesis, it was noted that neutralization of HMGB1, using anti-HMGB1 antibodies, abrogated BLP-associated lethality almost completely. To conclude, tolerization with BLP leads to a down-regulation of HMGB1, thus offering a novel means of targeting the latter. HMGB1 is also a mediator of lethality in BLP-related sepsis.Language
engISSN
0741-5400 (Print)0741-5400 (Linking)
ae974a485f413a2113503eed53cd6c53
10.1189/jlb.0806504
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