Leukotriene B4/antimicrobial peptide LL‐37 proinflammatory circuits are mediated by BLT1 and FPR2/ALX and are counterregulated by lipoxin A4 and resolvin E1

• Published in: The FASEB journal 2011-05, Vol.25 (5), p.1697-1705
• Main Authors: Wan, Min, Godson, Catherine, Guiry, Patrick J., Agerberth, Birgitta, Haeggström, Jesper Z.
• Format: Article
• Language: English
• Subjects: Antimicrobial Cationic Peptides - pharmacology; Blotting, Western; Calcium - metabolism; cathelicidin; Cells, Cultured; eicosanoid; Eicosapentaenoic Acid - analogs & derivatives; Eicosapentaenoic Acid - pharmacology; Electrophoresis, Polyacrylamide Gel; Group IV Phospholipases A2 - metabolism; Humans; Immunoenzyme Techniques; inflammation; Leukotriene B4 - metabolism; Lipoxins - pharmacology; Medicin och hälsovetenskap; Neutrophils - drug effects; Neutrophils - metabolism; Receptors, Formyl Peptide - metabolism; Receptors, Leukotriene B4 - metabolism; Receptors, Lipoxin - metabolism; resolution
• ISSN: 0892-6638; 1530-6860; 1530-6860
• DOI: 10.1096/fj.10-175687

ABSTRACT In humans, the antimicrobial peptide LL‐37 and leukotriene B4 (LTB4) are important proinflammatory mediators, whereas lipoxin A4 (LXA4) and resolvin E1 (RvE1) possess anti‐inflammatory, prore‐solving 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 proin‐flammatory circuit might be inhibited by LXA4 and RvE1 acting at FPR2/ALX and BLT1, respectively, leading to dampened mediator release.—Wan, M., Godson, C., Guiry, P. J., Agerberth, B., Haeggström, J. Z. Leukotriene B4/antimicrobial peptide LL‐37 proinflammatory circuits are mediated by BLT1 and FPR2/ALX and are counterregulated by lipoxin A4 and resolvin E1. FASEB J. 25, 1697–1705 (2011). www.fasebj.org