These two authors contributed equally to this manuscript.
The antimicrobial peptide LL-37 induces synthesis and release of cysteinyl leukotrienes from human eosinophils – implications for asthma
Article first published online: 18 JAN 2013
© 2013 John Wiley & Sons A/S. Published by Blackwell Publishing Ltd
Volume 68, Issue 3, pages 304–311, March 2013
How to Cite
The antimicrobial peptide LL-37 induces synthesis and release of cysteinyl leukotrienes from human eosinophils – implications for asthma. Allergy 2013; 68: 304–311., , , .
Edited by: Hans-Uwe Simon
- Issue published online: 8 FEB 2013
- Article first published online: 18 JAN 2013
- Manuscript Accepted: 28 OCT 2012
- Swedish Research Council. Grant Numbers: 20854, 10350
- Swedish Strategic Foundation (SSF)
- Swedish Cancer Society
- Thorsten & Ragnar Söderberg's Foundation
- Swedish Heart Lung Foundation
- Stockholm County Council. Grant Number: 20090136
- Karolinska Institutet
- eosinophil cationic proteins;
- human primary eosinophils;
Eosinophils and their products, including leukotrienes and eosinophil cationic protein (ECP), are well-known mediators of inflammation and tissue damage in asthma. The antimicrobial peptide LL-37 exhibits a variety of immunomodulatory activities. However, the role of LL-37 in asthma has not been fully addressed. Here, we aim to investigate the effect of LL-37 on inducing inflammatory mediators in human eosinophils, probe the underlying mechanisms, and search for a clinical correlate.
Primary eosinophils were isolated from peripheral blood. Leukotriene and ECP levels were measured using EIAs or ELISAs. Activation of leukotriene-synthesizing enzymes and signaling kinases was analyzed by Western blot or immunofluorescent imaging. LL-37/its proform hCAP18 expression was analyzed by Western blot.
LL-37, via formyl peptide receptor-2 (FPR-2), triggered the release of cysteinyl leukotrienes (cys-LTs) from eosinophils. The release was more prominent in cells primed with the eosinophilopoietic cytokine GM-CSF or IL-5 or cells from asthmatic patients. LL-37 stimulates lipid body formation and activates cys-LT-synthesizing enzymes by multiple mechanisms: enhancing cPLA2 activity by pERK1/2-mediated phosphorylation and inducing intracellular translocation and assembly of 5-LO and LTC4S at perinuclear locations and lipid bodies. In addition to cys-LTs, LL-37 enhances ECP release from eosinophils via pERK1/2. The expression of hCAP18 and its release following leukotriene stimulation are significantly higher in eosinophils from asthmatics.
This study identifies LL-37 as an eosinophil-activating peptide that triggers release of inflammatory mediators. The clinical correlation suggests that LL-37/hCAP18 and its signaling pathway represent potential therapeutic targets for this disease.