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

Shock. 2009 Mar;31(3):280-4. doi: 10.1097/SHK.0b013e318186262d.


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.

MeSH terms

  • 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*


  • Cytokines
  • HMGB1 Protein
  • Inflammation Mediators
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic
  • Tlr2 protein, mouse
  • Tlr4 protein, mouse
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • antithrombin III-protease complex
  • Antithrombin III
  • Peptide Hydrolases