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Leukotriene B₄ Triggers the In Vitro and In Vivo Release of Potent Antimicrobial Agents¹

Louis Flamand^2,*, Michel J. Tremblay and Pierre Borgeat^*

^* Rheumatology and Immunology Research Center and Research Center in Infectious Diseases, Centre Hospitalier Universitaire de Québec Research Center and Laval University, Quebec, Canada

Leukotriene B₄ (LTB₄) is a bioactive lipid derived from the metabolism of arachidonic acid. Mainly produced by polymorphonuclear leukocytes (PMN) and macrophages, LTB₄ 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 LTB₄, 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 LTB₄-activated PMN lead to 90% reduction in infectivity. ELISA and mass spectroscopy analysis of proteins released from LTB₄-activated PMN have identified several antimicrobial proteins, including -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 LTB₄ (50 µg/kg) to monkeys led to an increase in -defensin plasmatic levels and enhanced ex vivo antimicrobial activities of plasma. These results demonstrate the ability of LTB₄ 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 LTB₄ in host defense.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Innatis Pharma. L.F. is a senior scholar from the Fonds de la Recherche en Santé du Québec and M.J.T. holds the Canada Research Chair in Human Immuno-Retrovirology (tier 1 level).

² Address correspondence and reprint requests to Dr. Louis Flamand, Rheumatology and Immunology Research Center, Centre Hospitalier Universitaire de Québec Research Center, Centre Hospitalier de l’Université Laval (CHUL), Room T1-49, 2705 Laurier Boulevard, Sainte-Foy, Québec, Canada. E-mail address: Louis.flamand{at}crchul.ulaval.ca

³ Abbreviations used in this paper: PMN, polymorphonuclear leukocyte; LB, Luria-Bertani; LT, leukotriene.