Dual role of lipopolysaccharide (LPS)-binding protein in neutralization ofLPS and enhancement of LPS-induced activation of mononuclear cells

The lipopolysaccharide (LPS)-binding protein (LBP) has a concentration-depe ndent dual role in the pathogenesis of gram-negative sepsis: low concentrat ions of LBP enhance the LPS-induced activation of mononuclear cells (MNC), whereas the acute-phase rise in LBP concentrations inhibits LPS-induced cel lular stimulation. In stimulation experiments, we have found that LBP media tes the LPS-induced cytokine release from MNC even under serum-free conditi ons. In biophysical experiments we demonstrated that LBP binds and intercal ates into lipid membranes, amplified by negative charges of the latter, and that intercalated LBP can mediate the CD14-independent intercalation of LP S into membranes in a lipid-specific and temperature-dependent manner. In c ontrast, prior complexation of LBP and LPS inhibited binding of these compl exes to membranes due to different binding of LBP to LPS or phospholipids. This results in a neutralization of LPS and, therefore, to a reduced produc tion of tumor necrosis factor by MNC. We propose that LBP is not only prese nt as a soluble protein in the serum but may also be incorporated as a tran smembrane protein in the cytoplasmic membrane of MNC and that the interacti on of LPS with membrane-associated LBP may be an important step in LBP-medi ated activation of MNC, whereas LBP-LPS complexation in the serum leads to a neutralization of LPS.