Abstract
Stearoyl lysophosphatidylcholine (LPC) has recently been proven protective against lethal sepsis by stimulating neutrophils to eliminate invading pathogens through an H2O2-dependent mechanism. Here, we demonstrate that stearoyl LPC, but not caproyl LPC, significantly attenuates circulating high-mobility group box 1 (HMGB1) levels in endotoxemia and sepsis by suppressing endotoxin-induced HMGB1 release from macrophages/monocytes. Neutralizing antibodies against G2A, a potential cell surface receptor for LPC, partially abrogated stearoyl LPC-mediated suppression of HMGB1 release. Thus, stearoyl LPC confers protection against lethal experimental sepsis partly by facilitating the elimination of the invading pathogens and partly by inhibiting endotoxin-induced release of a late proinflammatory cytokine, HMGB1.
Highlights
Stearoyl lysophosphatidylcholine (LPC) has recently been proven protective against lethal sepsis by stimulating neutrophils to eliminate invading pathogens through an H2O2-dependent mechanism
Stearoyl LPC has recently been proven protective against lethal experimental sepsis by stimulating neutrophils to destroy ingested bacteria in an H2O2dependent mechanism (18)
To gain further insight into the protective mechanisms of LPC action in systemic inflammatory diseases, we evaluated the effects of various LPC species on the systemic accumulation of high-mobility group box 1 (HMGB1), a newly identified late mediator of endotoxemia and sepsis (3, 5, 13, 14)
Summary
Primary peritoneal macrophages were isolated from Balb/C mice (male, 7–8 weeks, 20–25 g) at 3 days after intraperitoneal injection of 2 ml of thioglycollate broth (4%) as described previously (6, 7). Thioglycollate-elicited macrophages were resuspended in RPMI 1640 medium supplemented with 10% fetal calf serum and immediately transferred onto six-well tissue culture plates (4 ϫ 106 cells/2 ml/well). After preculture for 12 h, the adherent cells were gently washed with, and cultured in, serum-free OPTI-MEM I medium 2 h before lipopolysaccharide (LPS) stimulation. Human peripheral blood mononuclear cells were isolated by density gradient centrifugation through Ficoll (Ficoll-Paque PLUS; Pharmacia, Piscataway, NJ) as described previously (6, 19) and cultured in RPMI 1640 medium, 10% heat-inactivated human serum, and 2 mM l-glutamine overnight. Nonadherent cells were subsequently removed, and adherent monocyte-enriched cultures were stimulated with LPS
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