BIOCHEMICAL-CHARACTERIZATION OF RECOMBINANT FUSIONS OF LIPOPOLYSACCHARIDE-BINDING-PROTEIN AND BACTERICIDAL PERMEABILITY-INCREASING PROTEIN - IMPLICATIONS IN BIOLOGICAL-ACTIVITY/

The physiological response to endotoxin (lipopolysaccharide (LPS)) can be regulated by two closely related LPS-binding proteins, LPS-binding protein (LBP), which potentiates LPS' inflammatory activity via inter action with the monocytic antigen CD14, and bactericidal/permeability- increasing protein (BPI), which neutralizes LPS. Both proteins bind LP S with high affinity sites in their N-terminal domains, whereas intera ction between LBP and CD14 is dependent upon the LBP C-terminal domain . We have created fusions of the N- and C-terminal domains from each p rotein and compared the functional activities and pharmacokinetics of these fusions, the individual N-terminal domains, and the parent prote ins. The N-terminal domains of BPI and LEP bound lipid A with their ch aracteristic apparent affinity constants, regardless of the C-terminal fusion partner. In addition, the C-terminal domain of LBP allowed tra nsfer of LPS to CD14 in conjunction with either N-terminal LPS binding domain. Proteins containing a EPI N-terminal domain had greater hepar in binding capacities in vitro and were cleared more rapidly from the plasma of whole animals. Taken together, these data better define how closely related proteins such as BPI and LBP can have opposing effects on the body's response to LPS.