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Published online before print July 11, 2007

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(Journal of Leukocyte Biology. 2007;82:906-914.)
© 2007 by Society for Leukocyte Biology

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

J. Calvin Coffey^*,1, Jiang Huai Wang^*,1,2, Ray Kelly, Laszlo Romics, Jr.^*, Adrian O'Callaghan^*, Carmen Fiuza and H. Paul Redmond^*

Departments of
^* Academic Surgery and
Medicine, University College Cork (UCC)/National University of Ireland (NUI), Cork University Hospital, Cork, Ireland; and
Department of Surgery, Queen's University Hospital, Nottingham, United Kingdom

² Correspondence: Department of Academic Surgery, University College Cork (UCC)/National University of Ireland (NUI), Cork University Hospital, Cork, Ireland. E-mail: jh.wang{at}ucc.ie

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.

Key Words: monocytes/macrophages • proinflammatory cytokines • DNA microarray • real-time RT-PCR • human • mice