Leukotriene B4 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 ( 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.