Premium
The antimicrobial peptide LL ‐37 induces synthesis and release of cysteinyl leukotrienes from human eosinophils – implications for asthma
Author(s) -
Sun J.,
Dahlén B.,
Agerberth B.,
Haeggström J. Z.
Publication year - 2013
Publication title -
allergy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.363
H-Index - 173
eISSN - 1398-9995
pISSN - 0105-4538
DOI - 10.1111/all.12087
Subject(s) - leukotriene , eosinophil , leukotriene c4 , western blot , lipid signaling , allergic inflammation , immunology , chemistry , intracellular , inflammation , microbiology and biotechnology , biology , asthma , biochemistry , gene
Background 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. Methods Primary eosinophils were isolated from peripheral blood. Leukotriene and ECP levels were measured using EIA s or ELISA s. Activation of leukotriene‐synthesizing enzymes and signaling kinases was analyzed by W estern blot or immunofluorescent imaging. LL ‐37/its proform hCAP 18 expression was analyzed by W estern blot. Results LL ‐37, via formyl peptide receptor‐2 ( FPR ‐2), triggered the release of cysteinyl leukotrienes (cys‐ LT s) 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 cPLA 2 activity by pERK 1/2‐mediated phosphorylation and inducing intracellular translocation and assembly of 5‐ LO and LTC 4 S at perinuclear locations and lipid bodies. In addition to cys‐LTs, LL‐37 enhances ECP release from eosinophils via pERK 1/2. The expression of hCAP 18 and its release following leukotriene stimulation are significantly higher in eosinophils from asthmatics. Conclusions This study identifies LL ‐37 as an eosinophil‐activating peptide that triggers release of inflammatory mediators. The clinical correlation suggests that LL ‐37/ hCAP 18 and its signaling pathway represent potential therapeutic targets for this disease.