LACTOFERRIN IS A LIPID A-BINDING PROTEIN

Lactoferrin (LF), a cationic 80-kDa protein present in polymorphonucle ar leukocytes and in mucosal secretions, is known to have antibacteria l effects on gram-negative bacteria, with a concomitant release of lip opolysaccharides (LPS, endotoxin). In addition, LF is known to decreas e LPS-induced cytokine release by monocytes and LPS priming of polymor phonuclear leukocytes. Its mechanism of action is incompletely underst ood. We have now demonstrated by in vitro-binding studies that LF bind s directly to isolated lipid A and intact LPS of clinically relevant s erotypes of the species which most frequently cause bacteremia (Escher ichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa), as wel l as to lipid A and LPS of mucosal pathogens (among others, Neisseria meningitides and Haemophilus influenzae). Binding to LPS was inhibitab le by lipid A and polymyxin B but not by KDO (3-deoxyy-D-manno-octulos onate), a glycoside residue present in the inner core of LPS. Binding of LF to lipid A was saturable, and an affinity constant of 2 x 10(9) M(-1) was calculated for the LF-lipid A interaction. Our data may expl ain, in part, the mechanism whereby LF exerts its antibacterial and an ti-endotoxic effects. Further studies on the ability of LF to block th e detrimental effects of LPS, both in vitro and in vivo, are warranted .