Regulation of the response to bacterial lipopolysaccharide by endogenous and exogenous lipopolysaccharide binding proteins.
Bactericidal/permeability-increasing protein (BPI) is a natural constituent of human neutrophils. Recombinant BPI has been shown to bind to bacterial lipopolysaccharide (LPS), and to neutralize the ability of LPS to stimulate inflammatory cells in vitro and in vivo. BPI shares sequence homology and immunocrossreactivity with another endogenous LPS binding protein, lipopolysaccharide binding protein (LBP). Despite the homology, these proteins have opposite effects on LPS. LBP mediates cell activation by low, otherwise nonstimulatory concentrations, while BPI neutralizes LPS bioactivity. Exogenous LPS binding proteins in the form of monoclonal antibodies have been developed with the goal of generating antiendotoxin therapeutics to treat gram-negative sepsis and related syndromes. Here we show that LPS-binding and neutralizing properties of BPI compare favorably with two monoclonal antibodies tested, HA-1A and XMMEN-OE5. BPI also competes effectively with LBP for LPS. Thus, BPI may represent an endogenous LPS-regulatory molecule suitable for use as a potent antiendotoxin therapeutic.
Marra
M N
MN
Incyte Pharmaceuticals, Palo Alto, Calif. 94304.
Thornton
M B
MB
Snable
J L
JL
Leong
S
S
Lane
J
J
Wilde
C G
CG
Scott
R W
RW
D000818:Animals; D023181:Antimicrobial Cationic Peptides; D001770:Blood Bactericidal Activity; D001798:Blood Proteins / Q000494:pharmacology*; D005260:Female; D006801:Humans; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors*; D008565:Membrane Proteins; D051379:Mice; D009504:Neutrophils; D010539:Permeability; D011971:Receptors, Immunologic / Q000187:drug effects*; D011994:Recombinant Proteins / Q000494:pharmacology
D023181:Antimicrobial Cationic Peptides; D001798:Blood Proteins; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D011971:Receptors, Immunologic; D011994:Recombinant Proteins; C021623:bactericidal permeability increasing protein