Abstract
SummaryHigh-mobility group box-1 (HMGB1) protein has been postulated to play a pathogenic role in severe sepsis. Histidine-rich glycoprotein (HRG), a 75 kDa plasma protein, was demonstrated to improve the survival rate of septic mice through the regulation of neutrophils and endothelium barrier function. As the relationship of HRG and HMGB1 remains poorly understood, we investigated the effects of HRG on HMGB1-mediated pathway in endothelial cells, focusing on the involvement of specific receptors for HRG. HRG potently inhibited the HMGB1 mobilization and effectively suppressed rHMGB1-induced inflammatory responses and expression of all three HMGB1 receptors in endothelial cells. Moreover, we first clarified that these protective effects of HRG on endothelial cells were mediated through C-type lectin domain family 1 member A (CLEC-1A) receptor. Thus, current study elucidates protective effects of HRG on vascular endothelial cells through inhibition of HMGB1-mediated pathways may contribute to the therapeutic effects of HRG on severe sepsis.
Highlights
High-mobility group box-1 (HMGB1), a nonhistone chromatin-binding nuclear protein, can be actively secreted into the extravascular space by several immune cell types or passively released by damaged tissues and necrotic cells (DeMarco et al, 2005; Andersson et al, 2000)
SUMMARY High-mobility group box-1 (HMGB1) protein has been postulated to play a pathogenic role in severe sepsis
As the relationship of Histidine-rich glycoprotein (HRG) and HMGB1 remains poorly understood, we investigated the effects of HRG on HMGB1-mediated pathway in endothelial cells, focusing on the involvement of specific receptors for HRG
Summary
High-mobility group box-1 (HMGB1), a nonhistone chromatin-binding nuclear protein, can be actively secreted into the extravascular space by several immune cell types or passively released by damaged tissues and necrotic cells (DeMarco et al, 2005; Andersson et al, 2000). Microvascular injury is one of the characteristics of sepsis-associated tissue damage that may be manifested by single or multiple organ failure syndromes (Lehr et al, 2000; Lentsch and Ward, 2000). HMGB1 was reported to have multiple proinflammatory effects on vascular endothelial cells by binding to three pathogen-associated cell surface pattern recognition receptors, thereby inducing tumor necrosis factor alpha (TNF-a) expression and NF-kB activation in target cells and stimulating the production of an array of proinflammatory cytokines (Abraham et al, 2000; Park et al, 2004; Lotze and Tracey, 2005; Fiuza et al, 2003; Treutiger et al, 2003; Mullins et al, 2004), which suggest an important role for HMGB1 in endothelial cell activation and injury in sepsis and systemic inflammation.
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