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 componen t of the granules of polymorphonuclear neutrophils (PMNs) and is invol ved in the killing of gram-negative bacteria. A 23-kd recombinant prot ein, 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 preven t 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 n ecrosis factor (TNF), interleukin-1beta (IL-1beta), IL-6, IL-8], induc ed by E. coli 0113 LPS, was markedly reduced by rBPI23 in a concentrat ion-dependent fashion. The production of the anti-inflammatory protein IL-1ra (IL-1 receptor antagonist) was triggered by lower LPS concentr ations than those necessary for the other cytokines. Furthermore, prev ention of IL-1ra release required higher rBPI23 concentrations than fo r other cytokines. The LPS-induced production of oxygen-derived free r adicals by phagocytic cells (resulting in chemiluminescence) was also prevented by rBPI23. The inhibition was specific for LPS because the a ctivation of leukocytes by phorbol myristate acetate, zymosan, or TNF was unaffected by BPI. The ability of rBPI23 to antagonize specificall y the effects of endotoxin in the complex environment of human blood a long with its bactericidal activity suggests that rBPI23 may be a nove l therapeutic agent in the treatment of gram-negative infections.