High concentrations of lipopolysaccharide-binding protein in serum of patients with severe sepsis or septic shock inhibit the lipopolysaccharide response in human monocytes

Lipopolysaccharide-binding protein (LBP), an acute-phase protein recognizin g lipopolysaccharide (LPS), catalyzes in low concentrations its transfer to the cellular LPS receptor consisting of CD14 and Toll-like receptor-4. It has recently been shown that high concentrations of recombinant LBP can pro tect mice in a peritonitis model from the lethal effects of LPS. To determi ne whether in humans the acute-phase rise of LBP concentrations can inhibit LPS binding to monocytes and induction of proinflammatory cytokines, LBP c oncentrations were analyzed in 63 patients meeting the American College of Chest Physicians/Society of Critical Care Medicine criteria of severe sepsi s or septic shock and the ability of these sera to modulate LPS effects In vitro was assessed employing different assays. Transfer of fluorescein isot hiocyanate-labeled LPS to human monocytes was assessed by a fluorescence-ac tivated cell sorter-based method, and activation of monocytes was investiga ted by measuring LPS-induced tumor necrosis factor-alpha secretion in the p resence of the sera. Anti-LBP antibodies and recombinant human LBP were ins trumental for depletion and reconstitution of acute-phase sera and subseque nt assessment of their modulating effects on LPS activity. Sera of patients with severe sepsis/septic shock exhibited a diminished LPS transfer activi ty and LPS-induced tumor necrosis factor-alpha secretion as compared with s era from healthy controls. LBP depletion of sepsis sera and addition of rhL BP resulting in concentrations found In severe sepsis confirmed that LBP wa s the major serum component responsible for the observed effects. In summar y, the Inhibition of LPS effects by high concentrations of LBP in acute-pha se serum, as described here, may represent a novel defense mechanism of the host In severe sepsis and during bacterial Infections. (C) 2001 by The Ame rican Society of Hematology.