BACTERICIDAL PERMEABILITY-INCREASING PROTEIN AND LIPOPOLYSACCHARIDE (LPS)-BINDING PROTEIN - LPS BINDING-PROPERTIES AND EFFECTS ON LPS-MEDIATED CELL ACTIVATION

We have previously shown that human bactericidal/ permeability-increas ing protein (BPI) is able to inhibit serum-dependent lipopolysaccharid e (LPS)-mediated activation of human monocytes and neutrophils in vitr o, and to counteract the lethal effects of LPS challenge in vivo. Lipo polysaccharide-binding protein (LBP) is a serum protein which particip ates in LPS-mediated activation of cells (Tobias, P. S., Mathison, J., Mintz, D., Lee, J. D., Kravchenko, V., Kato, K., Pugin, J., and Ulevi tch, R. J. (1992) Am. J. Respir: Cell. Mel. Biol. 7, 239-245). We have proposed that BPI functions in a negative feedback loop which opposes this activation (Marra, M. N., Wilde, C. G., Collins, M. S., Snable, J. L., Thornton, M. E., and Scott, R. W. (1992) J. Immunol. 148, 532-5 37). We have now cloned and expressed recombinant forms of human BPI a nd LBP. Here we demonstrate that purified recombinant human LBP can re place the serum requirement for both LPS binding to human monocytes an d LPS-mediated secretion of tumor necrosis factor alpha from these cel ls. These activities of LBP are inhibited by a neutralizing anti-CD14 monoclonal antibody. We further demonstrate that purified recombinant human BPI can inhibit LBP-mediated LPS binding to cells and their subs equent activation. Comparison of the LPS binding properties of BPI and LBP in enzyme-linked immunosorbent type assays and in the Limulus ame bocyte lysate assay suggest that BPI has a stronger affinity for LPS t han does LBP. Direct competition between BPI and LBP for LPS may ex pl ain the inhibition by EPI of the proinflammatory effects of LBP in the presence of LPS.