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 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
Min
M
Department of Medical Biochemistry and Biophysics, Division of Chemistry 2, Karolinska Institutet, S-171 77 Stockholm, Sweden.
Sabirsh
Alan
A
Wetterholm
Anders
A
Agerberth
Birgitta
B
Haeggström
Jesper Z
JZ
D023181:Antimicrobial Cationic Peptides / Q000378:metabolism*; D015153:Blotting, Western; D054804:Cathelicidins; D002851:Chromatography, High Pressure Liquid; D004797:Enzyme-Linked Immunosorbent Assay; D004926:Escherichia coli / Q000378:metabolism; D006801:Humans; D007975:Leukotriene B4 / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D010587:Phagocytosis; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D054645:Protein Phosphatase 1; D018102:Receptors, Leukotriene B4 / Q000378:metabolism*
D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; C513240:LTB4R protein, human; C485878:LTB4R2 protein, human; D018102:Receptors, Leukotriene B4; D007975:Leukotriene B4; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1