Antimicrobial and immunoregulatory functions of lactoferrin and its potential therapeutic application

Abstract

Lactoferrin is an iron-binding glycoprotein present in various secretions (eg. milk, tears, saliva,pancreatic juice, etc.). It is also stored in specific granules of polymorphonuclear granulocytes from which it is released following activation. Lactoferrin exerts a bactericidal activity by damaging the outermembrane of Gram-negative bacteria, as well as immunoregulatory functions by decreasing the release of interleukin-l (IL- 1), IL-2 and tumor necrosis factor-alpha INF-alpha) and enhancing monocyte and natural killer cell cytotoxicity. Lactoferrin binds with high affinity to lipid A, the toxic moiety of the lipopolysaccharide, or endotoxin from Gram-negative bacteria Lipopolysacchride interaction with monocytes/ma phages results in the production and release of TNF-alpha, that plays an important role in inducing septic shock In this respect, it has recently been demonstrated that lactoferrin inhibits the lipopolysaccharide interaction with CD14 on monocytes/macrophages by competition with the lipopolysaccharide binding protein. Therefore, besides its bactericidal activity, lactoferrin may also act by neutralizing the toxic effects of lipopolysaccharide and this protective role against endotoxin lethal shock has been demonstrated in animal models. Moreover, in vitro and in vivo neutralization of endotoxin by a human lactoferrin-derived peptide was also reported and lactoferrin or lactoferrin-derived peptides could represent useful tools for the treatment of endotoxin-induced septic hock. The recent production and characterization of monoclonal antibodies against different epitopes of human lactoferrin, including monoclonal antibodies selectively neutralizing lactoferrin binding to lipid A, may allow a better elucidation of the consequence of lactoferrin-lipopolysaccharide interaction.