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Leukotriene B₄ triggers release of the cathelicidin LL-37 from human neutrophils: novel lipid-peptide interactions in innate immune responses

Min Wan^*, Alan Sabirsh^*, Anders Wetterholm^*, Birgitta Agerberth and Jesper Z. Haeggström^*,1

Department of Medical Biochemistry and Biophysics, Divisions of
^* Chemistry 2 and

Chemistry 1, Karolinska Institutet, Stockholm, Sweden

¹Correspondence: Department of Medical Biochemistry and Biophysics, Division of Chemistry 2, Karolinska Institutet, S-171 77 Stockholm, Sweden. E-mail: jesper.haeggstrom{at}ki.se

In humans, the antimicrobial peptide LL-37 and the potent chemotactic lipid leukotriene B₄ (LTB₄) are important mediators of innate immunity and host defense. Here we show that LTB₄, at very low (1 nM) concentrations, strongly promotes release of LL-37 peptides from human neutrophils (PMNs) in a time- and dose-dependent manner, as determined by Western blot, enzyme-linked immunoassay (ELISA), and antibacterial activity. The LTB₄-induced LL-37 release is mediated by the BLT1 receptor, and protein phosphatase-1 (PP-1) inhibits the release by suppressing the BLT1-mediated exocytosis of PMN granules. Conversely, LL-37 elicits translocation of 5-lipoxygenase (5-LO) from the cytosol to the perinuclear membrane in PMNs and promotes the synthesis and release of LTB₄, particularly from cells primed with LPS or GM-CSF. Furthermore, LL-37 stimulates PMN phagocytosis of Escherichia coli particles, a functional response that is enhanced by LTB₄, especially in GM-CSF pretreated cells. In these cells, LL-37 also enhances LTB₄-induced phagocytosis. Hence, in human PMNs, positive feedback circuits exist between LL-37 and LTB₄ that reciprocally stimulate the release of these mediators with the potential for synergistic bioactions and enhanced immune responses. Moreover, these novel lipid-peptide signaling pathways may offer new opportunities for pharmacological intervention and treatment of chronic inflammatory diseases.—Wan, M., Sabirsh, A., Wetterholm, A., Agerberth, B., Haeggström, J. Z. Leukotriene B₄ triggers release of the cathelicidin LL-37 from human neutrophils: novel lipid-peptide interactions in innate immune responses.

Key Words: phagocytosis • inflammation