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

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.

• Authors: J Calvin Coffey, Jiang Huai Wang, Ray Kelly, Laszlo Romics Jr, Adrian O'Callaghan, Carmen Fiuza, H Paul Redmond
• Journal: Journal of leukocyte biology (J Leukoc Biol) Vol. 82 Issue 4 Pg. 906-14 (Oct 2007) ISSN: 0741-5400 [Print] United States
• PMID: 17626148 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies
• Bacterial Proteins
• HMGB1 Protein
• Lipoproteins

Topics

• 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)