Tolerization with BLP down-regulates HMGB1 a critical mediator of sepsis-related lethality.
AuthorsCoffey, J Calvin
Wang, Jiang Huai
Romics, Laszlo Jr
Redmond, H Paul
AffiliationDepartment of Academic Surgery, University College Cork (UCC)/National University, of Ireland (NUI), Cork University Hospital, Cork, Ireland.
*Immune Tolerance/drug effects
Sepsis/chemically induced/*immunology/metabolism/prevention & control
Transcription, Genetic/drug effects/immunology
MetadataShow full item record
CitationJ Leukoc Biol. 2007 Oct;82(4):906-14. Epub 2007 Jul 11.
JournalJournal of leukocyte biology
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.
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