title: The antimicrobial peptide LL-37 induces synthesis and release of cysteinyl leukotrienes from human eosinophils--implications for asthma.
abstract: 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 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.
  
  
  RESULTS
  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 cPLA(2)  activity by pERK1/2-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 pERK1/2. The expression of hCAP18 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/hCAP18 and its signaling pathway represent potential therapeutic targets for this disease.
authors: Division of Physiological Chemistry II, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
authors: J
authors: J
authors: Sun
authors: B
authors: B
authors: Dahlén
authors: B
authors: B
authors: Agerberth
authors: J Z
authors: JZ
authors: Haeggström
mesh_terms: D000328:Adult; D023181:Antimicrobial Cationic Peptides; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D001249:Asthma / Q000276:immunology* / Q000378:metabolism*; D054804:Cathelicidins / Q000494:pharmacology*; D003545:Cysteine / Q000276:immunology / Q000378:metabolism*; D047150:Eosinophil Cationic Protein / Q000378:metabolism; D004804:Eosinophils / Q000187:drug effects* / Q000276:immunology*; D005260:Female; D005982:Glutathione Transferase / Q000378:metabolism; D054513:Group IV Phospholipases A2 / Q000378:metabolism; D006801:Humans; D015289:Leukotrienes / Q000276:immunology / Q000378:metabolism*; D050356:Lipid Metabolism; D008297:Male; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D021381:Protein Transport / Q000187:drug effects; D044042:Receptors, Formyl Peptide / Q000378:metabolism; D044067:Receptors, Lipoxin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D055815:Young Adult
chemical_list: D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; C105101:FPR2 protein, human; D015289:Leukotrienes; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; C112381:cysteinyl-leukotriene; D001094:Arachidonate 5-Lipoxygenase; D005982:Glutathione Transferase; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D054513:Group IV Phospholipases A2; D047150:Eosinophil Cationic Protein; C041116:leukotriene-C4 synthase; D003545:Cysteine