title: Leukotriene B4/antimicrobial peptide LL-37 proinflammatory circuits are mediated by BLT1 and FPR2/ALX and are counterregulated by lipoxin A4 and resolvin E1.
abstract: In humans, the antimicrobial peptide LL-37 and leukotriene B(4) (LTB(4)) are important proinflammatory mediators, whereas lipoxin A(4) (LXA(4)) and resolvin E1 (RvE1) possess anti-inflammatory, proresolving properties. Previously, we reported that LTB(4) triggers LL-37 release from human neutrophils (PMNs) and, conversely, that LL-37 promotes LTB(4) production from these cells. Here we show that this effect of LL-37 is mediated via the GPCR FPR2/ALX. LL-37 (5-30 μg/ml) induces intracellular calcium mobilization in a dose-dependent manner, and the signal transduction leading to LTB(4) release involves p38 MAP kinase and phosphorylation of cPLA(2). LXA(4), an endogenous lipid ligand of FPR2/ALX, and a stable LXA(4) analog [benzo-LXA(4)] were ineffective as stimuli at the concentrations of 0.1-10 nM for LTB(4) release from PMNs. Likewise, the BLT1 ligand RvE1, a derivative of eicosapentaenoic acid, inhibited LTB(4)-induced LL-37 production from PMNs at 1-100 nM, whereas chemerin, a peptide ligand of the RvE1 receptor ChemR23, failed to block LTB(4)-induced LL-37 release at the same concentrations. Hence, in human neutrophils, binding of LL-37 to FPR2/ALX promotes LTB(4) production, which can bind to BLT1 and elicit further LL-37 release. This proinflammatory circuit might be inhibited by LXA(4) and RvE(1) acting at FPR2/ALX and BLT1, respectively, leading to dampened mediator release.
authors.affiliation: Division of Physiological Chemistry 2, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden.
authors.forename: Min
authors.initials: M
authors.lastname: Wan
authors.forename: Catherine
authors.initials: C
authors.lastname: Godson
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Guiry
authors.forename: Birgitta
authors.initials: B
authors.lastname: Agerberth
authors.forename: Jesper Z
authors.initials: JZ
authors.lastname: Haeggström
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology*; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D015118:Eicosapentaenoic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D004591:Electrophoresis, Polyacrylamide Gel; D054513:Group IV Phospholipases A2 / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D007975:Leukotriene B4 / Q000378:metabolism*; D044045:Lipoxins / Q000494:pharmacology*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D044042:Receptors, Formyl Peptide / Q000378:metabolism*; D018102:Receptors, Leukotriene B4 / Q000378:metabolism*; D044067:Receptors, Lipoxin / Q000378:metabolism*; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; C105101:FPR2 protein, human; C513240:LTB4R protein, human; D044045:Lipoxins; D044042:Receptors, Formyl Peptide; D018102:Receptors, Leukotriene B4; D044067:Receptors, Lipoxin; C040527:lipoxin A4; D007975:Leukotriene B4; D015118:Eicosapentaenoic Acid; D054513:Group IV Phospholipases A2; C499823:5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid; D002118:Calcium; D054804:Cathelicidins