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- Title
Leukotriene B<sub>4</sub>/antimicrobial peptide LL-37 proinflammatory circuits are mediated by BLT1 and FPR2/ALX and are counterregulated by lipoxin A<sub>4</sub> and resolvin E1.
- Authors
Min Wan; Godson, Catherine; Guiry, Patrick J.; Agerberth, Birgitta; Haeggström, Jesper Z.
- Abstract
In humans, the antimicrobial peptide LL-37 and leukotriene B4 (LTB4) are important proin-flammatory mediators, whereas lipoxin A4 (LXA4) and resolvin E1 (RvE1) possess anti-inflammatory, proresolving properties. Previously, we reported that LTB4 triggers LL-37 release from human neutrophils (PMNs) and, conversely, that LL-37 promotes LTB4 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 LTB4 release involves p38 MAP kinase and phosphorylation of cPLA2. LXA4, an endogenous lipid ligand of FPR2/ALX, and a stable LXA4 analog [benzo-LXA4] were ineffective as stimuli at the concentrations of 0.1-10 nM for LTB4 release from PMNs. Likewise, the BLT1 ligand RvE1, a derivative of eicosapentaenoic acid, inhibited LTB4-induced LL-37 production from PMNs at 1-100 nM, whereas chemerin, a peptide ligand of the RvE1 receptor ChemR23, failed to block LTB4-induced LL-37 release at the same concentrations. Hence, in human neutrophils, binding of LL-37 to FPR2/ALX promotes LTB4 production, which can bind to BLT1 and elicit further LL-37 release. This proinflammatory circuit might be inhibited by LXA4 and RvE1 acting at FPR2/ALX and BLT1, respectively, leading to dampened mediator release.
- Subjects
LEUKOTRIENES; ANTIMICROBIAL peptides; PHOSPHORYLATION; EICOSAPENTAENOIC acid; LIPOXINS
- Publication
FASEB Journal, 2011, Vol 25, Issue 5, p1697
- ISSN
0892-6638
- Publication type
Article
- DOI
10.1096/fj.10-175687