The antimicrobial peptide LL-37 enhances IL-8 release by human airway smooth muscle cells.
BACKGROUND
Human airway smooth muscle (HASM) cells release various chemokines that are involved in recruitment of inflammatory cells, which can be found within or in the vicinity of the airway smooth muscle layer in patients with inflammatory lung diseases. Inflammatory cells contain antimicrobial peptides including the cathelicidin LL-37 and neutrophil defensins (HNP1-3).


OBJECTIVE
The aim of the study was to determine the effects of antimicrobial peptides on IL-8 (CXC chemokine ligand 8) release by HASM cells, and to study the underlying mechanisms.


METHODS
Human airway smooth muscle cells were stimulated with LL-37 and HNP1-3, and IL-8 protein and mRNA levels were determined by sandwich ELISA and PCR. Phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 was detected by using Western blot.


RESULTS
LL-37 enhanced IL-8 release by HASM cells, which was dependent on ERK1/2 activation. Receptors known to be involved in LL-37-induced signaling, including the epidermal growth factor receptor and formyl peptide receptors, were not involved in LL-37 signaling in HASM cells. The purinergic receptor antagonist suramin did block LL-37-induced ERK1/2 phosphorylation and IL-8 release, and expression of mRNA for the purinergic receptor P2X(7) was detected in HASM cells. HNP1-3 did increase ERK1/2 phosphorylation, but did not enhance IL-8 release by HASM cells.


CONCLUSIONS
These data show that HASM cells respond to the antimicrobial peptide LL-37 by releasing IL-8, suggesting that LL-37 is a regulator of the inflammatory process in various inflammatory lung diseases by enhancing IL-8 production.


CONCLUSIONS
LL-37 released by inflammatory cells may amplify inflammation through induction of IL-8 release by airway smooth muscle.
Zuyderduyn
Suzanne
S
Department of Pulmonology, Leiden University Medical Center, The Netherlands. S.Zuyderduyn@lumc.nl
Ninaber
Dennis K
DK
Hiemstra
Pieter S
PS
Rabe
Klaus F
KF
D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism*; D008168:Lung / Q000201:enzymology / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000276:immunology / Q000378:metabolism*; D015854:Up-Regulation / Q000276:immunology*; D023084:alpha-Defensins / Q000502:physiology; D054804:Cathelicidins
D023181:Antimicrobial Cationic Peptides; D016209:Interleukin-8; D023084:alpha-Defensins; C406413:human neutrophil peptide 1; C406416:human neutrophil peptide 2; C406427:human neutrophil peptide 3; D054804:Cathelicidins