Regulation of the Response to Bacterial Lipopolysaccharide by Endogenous and Exogenous Lipopolysaccharide Binding Proteins

Abstract

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.

Functional and biochemical characterization of epithelial bactericidal/permeability-increasing protein

“…BPI's high affinity for the lipid A region of lipopolysaccharide (LPS) (16) in the gram-negative bacterial outer membrane is followed by a time-dependent penetration of the molecule to the bacterial inner membrane, where damage results in a loss of membrane integrity, dissipation of electrochemical gradients, and bacterial death (39). In addition, BPI is capable of inhibiting all of the many proinflammatory activities of LPS, including the induction of cytokine release, activation of neutrophil oxidase enzymes, and nitric oxide formation (6,32,40,63). This protein can also serve as an opsonin for phagocytosis of gram-negative bacteria by neutrophils (9,34).…”

Four Reasons to Consider a Novel Class of Innate Immune Molecules in the Oral Epithelium

“…In in vivo animals, BPI's role seems to be the mitigation of LBP-mediated cytokine release during an immune response. When released by neutrophils at the site of infection, BPI binds to LPS, preventing LPS from binding to LBP and thus dampening the immune response (Marra et al, 1994). A final function of BPI is to deliver bound LPS to phagocytic cells (Fig.…”

Expression of BPI (bactericidal/permeability-increasing protein) in human mucosal epithelia

“…Thus BPI is capable of inhibiting all of the many pro-inflammatory activities of LPS, including induction of cytokine release, activation of the neutrophil oxidase enzyme, nitric oxide formation, etc. [22,23,25,26].…”