Human cathelicidin LL-37 is a chemoattractant for eosinophils and neutrophils that acts via formyl-peptide receptors.
BACKGROUND
Inflammatory lung diseases such as asthma and chronic obstructive pulmonary disease (COPD) are characterized by the presence of eosinophils and neutrophils. However, the mechanisms that mediate the influx of these cells are incompletely understood. Neutrophil products, including neutrophil elastase and antimicrobial peptides such as neutrophil defensins and LL-37, have been demonstrated to display chemotactic activity towards cells from both innate and adaptive immunity. However, chemotactic activity of LL-37 towards eosinophils has not been reported. Therefore, the aim of the present study was to investigate the chemotactic activity of LL-37 for eosinophils and to explore the mechanisms involved in LL-37-mediated attraction of neutrophils and eosinophils.


METHODS
Neutrophils and eosinophils were obtained from venous blood of healthy donors. Chemotaxis was studied using a modified Boyden chamber technique. Involvement of formyl-peptide receptors (FPRs) was studied using the antagonistic peptide tBoc-MLP. Activation of the mitogen-activated protein kinase (MAPK) ERK1/2 was studied by Western blotting using antibodies directed against phosphorylated ERK1/2.


RESULTS
Our results show that LL-37 chemoattracts both eosinophils and neutrophils. The FPR antagonistic peptide tBoc-MLP inhibited LL-37-induced chemotaxis. Whereas the FPR agonist fMLP activated ERK1/2 in neutrophils, LL-37 did not, indicating that fMLP and LL-37 deliver different signals through FPRs.


CONCLUSIONS
LL-37 displays chemotactic activity for eosinophils and neutrophils, and this activity is mediated via an FPR. These results suggest that LL-37 may play a role in inflammatory lung diseases such as asthma and COPD.
Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands.
G Sandra
GS
Tjabringa
Dennis K
DK
Ninaber
Jan Wouter
JW
Drijfhout
Klaus F
KF
Rabe
Pieter S
PS
Hiemstra
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects* / Q000276:immunology; D004789:Enzyme Activation; D004804:Eosinophils / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D004983:Ethanolamines / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D000068759:Formoterol Fumarate; D006801:Humans; D008969:Molecular Sequence Data; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology; D037342:Pertussis Toxin / Q000494:pharmacology; D044042:Receptors, Formyl Peptide / Q000276:immunology*; D054804:Cathelicidins
D000318:Adrenergic beta-Agonists; D000911:Antibodies, Monoclonal; D023181:Antimicrobial Cationic Peptides; D004983:Ethanolamines; D044042:Receptors, Formyl Peptide; D009240:N-Formylmethionine Leucyl-Phenylalanine; D037342:Pertussis Toxin; D048049:Extracellular Signal-Regulated MAP Kinases; C117062:Mapk15 protein, rat; D000068759:Formoterol Fumarate; D054804:Cathelicidins