The antimicrobial peptide LL-37 activates innate immunity at the airway epithelial surface by transactivation of the epidermal growth factor receptor.
Antimicrobial peptides produced by epithelial cells and neutrophils represent essential elements of innate immunity, and include the defensin and cathelicidin family of antimicrobial polypeptides. The human cathelicidin cationic antimicrobial protein-18 is an antimicrobial peptide precursor predominantly expressed in neutrophils, and its active peptide LL-37 is released from the precursor through the action of neutrophil serine proteinases. LL-37 has been shown to display antimicrobial activity against a broad spectrum of microorganisms, to neutralize LPS bioactivity, and to chemoattract neutrophils, monocytes, mast cells, and T cells. In this study we show that LL-37 activates airway epithelial cells as demonstrated by activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) and increased release of IL-8. Epithelial cell activation was inhibited by the MAPK/ERK kinase (MEK) inhibitors PD98059 and U0126, by the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor AG1478, by blocking anti-EGFR and anti-EGFR-ligand Abs, and by the metalloproteinase inhibitor GM6001. These data suggest that LL-37 transactivates the EGFR via metalloproteinase-mediated cleavage of membrane-anchored EGFR-ligands. LL-37 may thus constitute one of the mediators by which neutrophils regulate epithelial cell activity in the lung.
Tjabringa
G Sandra
GS
Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands. G.S.Tjabringa@LUMC.nl
Aarbiou
Jamil
J
Ninaber
Dennis K
DK
Drijfhout
Jan Wouter
JW
Sørensen
Ole E
OE
Borregaard
Niels
N
Rabe
Klaus F
KF
Hiemstra
Pieter S
PS
D000595:Amino Acid Sequence; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology*; D054804:Cathelicidins; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects; D016209:Interleukin-8 / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology*; D048670:MAP Kinase Kinase 4; D045726:Metalloproteases / Q000378:metabolism / Q000502:physiology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism / Q000502:physiology; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology; D008969:Molecular Sequence Data; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology*; D015533:Transcriptional Activation / Q000187:drug effects* / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases
D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D016209:Interleukin-8; D066246:ErbB Receptors; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D045726:Metalloproteases