Leukotriene B 4 triggers release of the cathelicidin LL‐37 from human neutrophils: novel lipid‐peptide interactions in innate immune responses

In humans, the antimicrobial peptide LL‐37 and the potent chemotactic lipid leukotriene B 4 (LTB 4 ) are important mediators of innate immunity and host defense. Here we show that LTB 4 , 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 LTB 4 ‐induced LL‐37 release is mediated by the BLT1 receptor, and protein phosphatase‐1 (PP‐1) inhibits the release by suppressing the BLTl‐mediated exocytosis of PMN granules. Conversely, LL‐37 elicits translocation of 5‐lipoxygen‐ase (5‐LO) from the cytosol to the perinuclear membrane in PMNs and promotes the synthesis and release of LTB 4 , 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 LTB 4 , especially in GM‐CSF pretreated cells. In these cells, LL‐37 also enhances LTB 4 ‐induced phagocytosis. Hence, in human PMNs, positive feedback circuits exist between LL‐37 and LTB 4 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., Haegg‐ström, J. Z. Leukotriene B4 triggers release of the cathelicidin LL‐37 from human neutrophils: novel lipid‐peptide interactions in innate immune responses. FASEB J. 21, 2897–2905 (2007)