Lipopolysaccharide-binding protein and phospholipid transfer protein release lipopolysaccharides from gram-negative bacterial membranes

Although animals mobilize their innate defenses against gram-negative bacte ria when they sense the lipid A moiety of bacterial lipopolysaccharide (LPS ), excessive responses to this conserved bacterial molecule can be harmful. Of the known ways for decreasing the stimulatory potency of LPS in blood, the binding and neutralization of LPS by plasma lipoproteins is most promin ent. The mechanisms by which host lipoproteins take up the native LPS that is found in bacterial membranes are poorly understood, however, since almos t all studies of host-LPS interactions have used purified LPS aggregates. U sing native Salmonella enterica serovar Typhimurium outer membrane fragment s (blebs) that contained H-3-labeled lipopolysaccharide (LPS) and S-35-labe led protein, we found that two human plasma proteins, LPS-binding protein ( LBP) and phospholipid transfer protein (PLTP), can extract [H-3]LPS from ba cterial membranes and transfer it to human high-density lipoproteins (HDL). Soluble CD14 (sCD14) did not release LPS from blebs get could facilitate L BP-mediated LPS transfer to HDL. LBP, but not PLTP, also promoted the activ ation of human monocytes by bleb-derived LPS. Whereas depleting or neutrali zing LBP significantly reduced LPS transfer from blebs to lipoproteins in n ormal human serum, neutralizing serum PLTP had no demonstrable effect. Of t he known lipid transfer proteins, LBP is thus most able to transfer LPS fro m bacterial membranes to the lipoproteins in normal human serum.