Role of toll-like receptors 2 and 4, and the receptor for advanced glycation end products in high-mobility group box 1-induced inflammation in vivo

High-mobility group box 1 (HMGB-1) has been reported as a "late" proinflammatory mediator in sepsis. In vitro data have shown that HMGB-1 can induce activation of intracellular signaling pathways via interaction with at least three pattern recognition receptors: Toll-like receptor (TLR) 2,...

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Published in:Shock (Augusta, Ga.) Vol. 31; no. 3; p. 280
Main Authors: van Zoelen, Marieke A D, Yang, Huan, Florquin, Sandrine, Meijers, Joost C M, Akira, Shizuo, Arnold, Bernd, Nawroth, Peter P, Bierhaus, Angelika, Tracey, Kevin J, van der Poll, Tom
Format: Journal Article
Language:English
Published: United States 01.03.2009
Subjects:
Animals
Antithrombin III - genetics
Antithrombin III - metabolism
Cytokines - genetics
Cytokines - metabolism
Female
HMGB1 Protein - toxicity
Inflammation - chemically induced
Inflammation - genetics
Inflammation - metabolism
Inflammation - mortality
Inflammation Mediators - toxicity
Male
Mice
Mice, Knockout
Neutrophils - metabolism
Neutrophils - pathology
Peptide Hydrolases - genetics
Peptide Hydrolases - metabolism
Receptor for Advanced Glycation End Products
Receptors, Immunologic - genetics
Receptors, Immunologic - metabolism
Time Factors
Toll-Like Receptor 2 - genetics
Toll-Like Receptor 2 - metabolism
Toll-Like Receptor 4 - genetics
Toll-Like Receptor 4 - metabolism
ISSN:1540-0514, 1540-0514
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Summary:High-mobility group box 1 (HMGB-1) has been reported as a "late" proinflammatory mediator in sepsis. In vitro data have shown that HMGB-1 can induce activation of intracellular signaling pathways via interaction with at least three pattern recognition receptors: Toll-like receptor (TLR) 2, TLR-4, and the receptor for advanced glycation end products (RAGE). The objective of this study was to investigate the role of these receptors in the in vivo response to HMGB-1. Therefore, we first performed a time-series experiment with wild-type (Wt) mice. High-mobility group box 1 induced time-dependent elevations of TNF-alpha, IL-6, monocyte chemoattractant protein 1, and thrombin-antithrombin complex levels in peritoneal lavage fluid and plasma. This inflammatory reaction was accompanied by a prominent and sustained rise in neutrophil counts in the peritoneal cavity. We next administered HMGB-1 to Wt, TLR-2, TLR-4, and RAGE mice. All genotypes showed similar plasma levels of TNF-alpha, IL-6, IL-10, and thrombin-antithrombin complex at 2 h after intraperitoneal injection of HMGB-1. Compared with Wt mice, both TLR-4 and RAGE mice displayed lower TNF-alpha and IL-6 concentrations and lower neutrophil numbers in their peritoneal lavage fluid. In contrast, TLR-2 mice showed increased levels of TNF-alpha and IL-6 in their peritoneal cavity relative to Wt mice. These data indicate that HMGB-1 induces release of cytokines, activation of coagulation, and neutrophil recruitment in vivo via a mechanism that at least in part depends on TLR-4 and RAGE.
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ISSN:1540-0514
1540-0514
DOI:10.1097/SHK.0b013e318186262d