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    Keywords: IN-VITRO ; IN-VIVO ; PATHWAY ; VITRO ; DISEASE ; PROTEIN ; SURGERY ; MICE ; ACTIVATION ; COMPLEX ; MECHANISM ; cytokines ; PLASMA ; RAGE ; inflammation ; INJURY ; signaling ; CYTOKINE ; GENOTYPE ; toll-like receptor 4 ; INVESTIGATE ; sepsis ; TLR2 ; toll-like receptor 2 ; HMGB-1 ; HMGB1 ; host defense ; receptor for advanced glycation end products
    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 TNIF-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
    Type of Publication: Journal article published
    PubMed ID: 19218854
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