Tolerization with BLP down-regulates HMGB1 a critical mediator of sepsis-related lethality.

Hdl Handle:
http://hdl.handle.net/10147/209271
Title:
Tolerization with BLP down-regulates HMGB1 a critical mediator of sepsis-related lethality.
Authors:
Coffey, J Calvin; Wang, 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.
Citation:
J Leukoc Biol. 2007 Oct;82(4):906-14. Epub 2007 Jul 11.
Journal:
Journal of leukocyte biology
Issue Date:
3-Feb-2012
URI:
http://hdl.handle.net/10147/209271
DOI:
10.1189/jlb.0806504
PubMed ID:
17626148
Abstract:
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:
eng
MeSH:
Animals; Antibodies/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
ISSN:
0741-5400 (Print); 0741-5400 (Linking)

Full metadata record

DC FieldValue Language
dc.contributor.authorCoffey, J Calvinen_GB
dc.contributor.authorWang, Jiang Huaien_GB
dc.contributor.authorKelly, Rayen_GB
dc.contributor.authorRomics, Laszlo Jren_GB
dc.contributor.authorO'Callaghan, Adrianen_GB
dc.contributor.authorFiuza, Carmenen_GB
dc.contributor.authorRedmond, H Paulen_GB
dc.date.accessioned2012-02-03T15:16:48Z-
dc.date.available2012-02-03T15:16:48Z-
dc.date.issued2012-02-03T15:16:48Z-
dc.identifier.citationJ Leukoc Biol. 2007 Oct;82(4):906-14. Epub 2007 Jul 11.en_GB
dc.identifier.issn0741-5400 (Print)en_GB
dc.identifier.issn0741-5400 (Linking)en_GB
dc.identifier.pmid17626148en_GB
dc.identifier.doi10.1189/jlb.0806504en_GB
dc.identifier.urihttp://hdl.handle.net/10147/209271-
dc.description.abstractTolerization 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.en_GB
dc.language.isoengen_GB
dc.subject.meshAnimalsen_GB
dc.subject.meshAntibodies/pharmacologyen_GB
dc.subject.meshBacterial Proteins/*toxicityen_GB
dc.subject.meshCell Lineen_GB
dc.subject.meshDown-Regulation/drug effects/immunologyen_GB
dc.subject.meshHMGB1 Protein/biosynthesis/*immunologyen_GB
dc.subject.meshHumansen_GB
dc.subject.mesh*Immune Tolerance/drug effectsen_GB
dc.subject.meshLipoproteins/*toxicityen_GB
dc.subject.meshMacrophages, Peritoneal/*immunology/metabolism/pathologyen_GB
dc.subject.meshMaleen_GB
dc.subject.meshMiceen_GB
dc.subject.meshSepsis/chemically induced/*immunology/metabolism/prevention & controlen_GB
dc.subject.meshTranscription, Genetic/drug effects/immunologyen_GB
dc.titleTolerization with BLP down-regulates HMGB1 a critical mediator of sepsis-related lethality.en_GB
dc.contributor.departmentDepartment of Academic Surgery, University College Cork (UCC)/National University, of Ireland (NUI), Cork University Hospital, Cork, Ireland.en_GB
dc.identifier.journalJournal of leukocyte biologyen_GB
dc.description.provinceMunster-

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