Leukotriene B4 Triggers the In Vitro and In Vivo Release of Potent Antimicrobial Agents

Leukotriene B(4) (LTB(4)) is a bioactive lipid derived from the metabolism of arachidonic acid. Mainly produced by polymorphonuclear leukocytes (PMN) and macrophages, LTB(4) triggers several functional responses important in host defense, including the secretion of lysosomal enzymes, the activation of NADPH oxidase activity, NO formation, and phagocytosis. We report that LTB(4), but not structural analogs thereof, stimulates primed human PMN to release molecules having potent antimicrobial activities. Exposure of bacteria (Escherichia coli and Staphylococcus aureus) or viruses (herpes simplex virus type 1 and HIV type 1) to supernatants of LTB(4)-activated PMN led to > or =90% reduction in infectivity. ELISA and mass spectroscopy analysis of proteins released from LTB(4)-activated PMN have identified several antimicrobial proteins, including alpha-defensins, cathepsin G, elastase, lysozyme C, and LL-37, that are likely to participate in the killing of microorganisms. In addition to these in vitro observations, i.v. injections of LTB(4) (50 microg/kg) to monkeys led to an increase in alpha-defensin plasmatic levels and enhanced ex vivo antimicrobial activities of plasma. These results demonstrate the ability of LTB(4) to cause the release of potent antimicrobial agents from PMN in vitro as well as in vivo and add further support to the important role of LTB(4) in host defense.