A recombinant amino terminal fragment of bactericidal/permeability-increasing protein inhibits the induction of leukocyte responses by LPS.
Bactericidal/permeability-increasing protein (BPI) is a major component of the granules of polymorphonuclear neutrophils (PMNs) and is involved in the killing of gram-negative bacteria. A 23-kd recombinant protein, corresponding to the NH2-terminal fragment of human BPI (rBPI23), has been shown to bind lipid A and antagonize some lipopolysaccharide (LPS)-mediated effects. In this study the ability of rBPI23 to prevent a wide range of cellular responses to LPS was investigated. In vitro assays were carried out using human blood to more closely approximate in vivo conditions. The release of proinflammatory cytokines [tumor necrosis factor (TNF), interleukin-1 beta (IL-1 beta), IL-6, IL-8], induced by E. coli O113 LPS, was markedly reduced by rBPI23 in a concentration-dependent fashion. The production of the anti-inflammatory protein IL-1ra (IL-1 receptor antagonist) was triggered by lower LPS concentrations than those necessary for the other cytokines. Furthermore, prevention of IL-1ra release required higher rBPI23 concentrations than for other cytokines. The LPS-induced production of oxygen-derived free radicals by phagocytic cells (resulting in chemiluminescence) was also prevented by rBPI23. The inhibition was specific for LPS because the activation of leukocytes by phorbol myristate acetate, zymosan, or TNF was unaffected by BPI. The ability of rBPI23 to antagonize specifically the effects of endotoxin in the complex environment of human blood along with its bactericidal activity suggests that rBPI23 may be a novel therapeutic agent in the treatment of gram-negative infections.
Mészáros
K
K
XOMA Corporation, Berkeley, California 94710.
Parent
J B
JB
Gazzano-Santoro
H
H
Little
R
R
Horwitz
A
A
Parsons
T
T
Theofan
G
G
Grinna
L
L
Weickmann
J
J
Elsbach
P
P
D023181:Antimicrobial Cationic Peptides; D001770:Blood Bactericidal Activity; D001798:Blood Proteins / Q000737:chemistry* / Q000494:pharmacology; D016207:Cytokines / Q000097:blood; D006801:Humans; D007962:Leukocytes / Q000187:drug effects / Q000502:physiology*; D008050:Lipid A / Q000097:blood; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D008163:Luminescent Measurements; D008565:Membrane Proteins; D010446:Peptide Fragments / Q000494:pharmacology*; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors; D011994:Recombinant Proteins / Q000494:pharmacology
D023181:Antimicrobial Cationic Peptides; D001798:Blood Proteins; D016207:Cytokines; D008050:Lipid A; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D010446:Peptide Fragments; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; C021623:bactericidal permeability increasing protein