science pharmaceutical expo biotech jobs
Originally published online as doi:10.1189/jlb.0108030 on August 7, 2008

Published online before print August 7, 2008
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
jlb.0108030v1
84/5/1326    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Aneja, R. K.
Right arrow Articles by Fink, M. P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Aneja, R. K.
Right arrow Articles by Fink, M. P.
(Journal of Leukocyte Biology. 2008;84:1326-1334.)
© 2008 by Society for Leukocyte Biology

Preconditioning with high mobility group box 1 (HMGB1) induces lipopolysaccharide (LPS) tolerance

Rajesh K. Aneja*,1, Allan Tsung{dagger}, Hanna Sjodin*, Julia V. Gefter{ddagger}, Russell L. Delude{ddagger}, Timothy R. Billiar{dagger} and Mitchell P. Fink§

* Departments of Critical Care Medicine and Pediatrics, Children’s Hospital of Pittsburgh,
{dagger} Surgery,
{ddagger} Critical Care Medicine and Pathology, and
§ Critical Care Medicine, Surgery and Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA

1 Correspondence: Department of Critical Care Medicine, University of Pittsburgh School of Medicine and Children’s Hospital of Pittsburgh, 3705 5th Ave., Pittsburgh, PA 15213, USA. E-mail: anejar{at}upmc.edu

High mobility group box protein 1 (HMGB1) modulates the innate immune response when present in the extracellular compartment. Receptors for HMGB1 include TLR4, TLR2, and the receptor for advanced glycation end products (RAGE). We tested the hypothesis that extracellular HMGB1 can induce LPS tolerance. HMGB1 dose-response experiments were performed on IFN-{gamma}-differentiated human monocyte-like THP-1 cells. Treatment with 1 µg/ml HMGB1 18 h before exposure to LPS (1 µg/ml) decreased TNF release, NF-{kappa}B nuclear DNA-binding activity, phosphorylation, and degradation of I{kappa}B{alpha}. Preconditioning with HMGB1 alone and HMGB1 in the presence of polymyxin B decreased LPS-mediated, NF-{kappa}B-dependent luciferase reporter gene expression. The specificity of HMGB1 in tolerance induction was supported further by showing that boiled HMGB1 failed to induce tolerance, and antibodies against HMGB1 blocked the induction of LPS tolerance. Bone marrow-derived macrophages obtained from C57Bl/6 wild-type mice became LPS-tolerant following HMGB1 exposure ex vivo, but macrophages derived from RAGE-deficient mice failed to develop tolerance and responded normally to LPS. Mice preconditioned with HMGB1 (20 µg) 1 h before LPS injection (10 mg/kg) had lower circulating TNF compared with control mice preconditioned with saline vehicle. Similarly, decreased nuclear DNA binding of hepatic NF-{kappa}B was observed in mice preconditioned with HMGB1. Taken together, these results suggest that extracellular HMGB1 induces LPS tolerance, and the RAGE receptor is required for this induction.

Key Words: signal transduction • RAGE • TLR




This article has been cited by other articles:


Home page
 Mol. Pharmacol.Home page
K. Tsoyi, T. Y. Lee, Y. S. Lee, H. J. Kim, H. G. Seo, J. H. Lee, and K. C. Chang
Heme-Oxygenase-1 Induction and Carbon Monoxide-Releasing Molecule Inhibit Lipopolysaccharide (LPS)-Induced High-Mobility Group Box 1 Release in Vitro and Improve Survival of Mice in LPS- and Cecal Ligation and Puncture-Induced Sepsis Model in Vivo
Mol. Pharmacol., July 1, 2009; 76(1): 173 - 182.
[Abstract] [Full Text] [PDF]