Tolerization with BLP down-regulates HMGB1 a critical mediator of sepsis-related lethality.
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.
Coffey
J Calvin
JC
Department of Academic Surgery, University College Cork (UCC)/National University of Ireland (NUI), Cork University Hospital, Cork, Ireland.
Wang
Jiang Huai
JH
Kelly
Ray
R
Romics
Laszlo
L
O'Callaghan
Adrian
A
Fiuza
Carmen
C
Redmond
H Paul
HP
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001426:Bacterial Proteins / Q000633:toxicity*; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects / Q000276:immunology; D024243:HMGB1 Protein / Q000096:biosynthesis / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects; D008074:Lipoproteins / Q000633:toxicity*; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018805:Sepsis / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism / Q000517:prevention & control; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology
D000906:Antibodies; D001426:Bacterial Proteins; D024243:HMGB1 Protein; D008074:Lipoproteins