title: 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.
abstract: 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.
authors.affiliation: Center for Infection and Immunity Amsterdam and daggerCenter for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. M.A.vanZoelen@amc.uva.nl
authors.forename: Marieke A D
authors.initials: MA
authors.lastname: van Zoelen
authors.forename: Huan
authors.initials: H
authors.lastname: Yang
authors.forename: Sandrine
authors.initials: S
authors.lastname: Florquin
authors.forename: Joost C M
authors.initials: JC
authors.lastname: Meijers
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Bernd
authors.initials: B
authors.lastname: Arnold
authors.forename: Peter P
authors.initials: PP
authors.lastname: Nawroth
authors.forename: Angelika
authors.initials: A
authors.lastname: Bierhaus
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Tracey
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
mesh_terms: D000818:Animals; D000990:Antithrombin III / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005260:Female; D024243:HMGB1 Protein / Q000633:toxicity*; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D018836:Inflammation Mediators / Q000633:toxicity*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: D016207:Cytokines; D024243:HMGB1 Protein; D018836:Inflammation Mediators; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C046193:antithrombin III-protease complex; D000990:Antithrombin III; D010447:Peptide Hydrolases