The antimicrobial peptide LL-37 activates innate immunity at the airway epithelial surface by transactivation of the epidermal growth factor receptor

G Sandra Tjabringa; Jamil Aarbiou; Dennis K Ninaber; Jan Wouter Drijfhout; Ole E Sørensen; Niels Borregaard; Klaus F Rabe; Pieter S Hiemstra

doi:10.4049/jimmunol.171.12.6690

The antimicrobial peptide LL-37 activates innate immunity at the airway epithelial surface by transactivation of the epidermal growth factor receptor

J Immunol. 2003 Dec 15;171(12):6690-6. doi: 10.4049/jimmunol.171.12.6690.

Authors

G Sandra Tjabringa¹, Jamil Aarbiou, Dennis K Ninaber, Jan Wouter Drijfhout, Ole E Sørensen, Niels Borregaard, Klaus F Rabe, Pieter S Hiemstra

Affiliation

¹ Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands. [email protected]

PMID: 14662872
DOI: 10.4049/jimmunol.171.12.6690

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Antimicrobial Cationic Peptides / pharmacology*
Cathelicidins
Cell Line, Tumor
Cells, Cultured
Enzyme Activation / drug effects
Enzyme Activation / physiology
ErbB Receptors / genetics*
ErbB Receptors / metabolism*
ErbB Receptors / physiology
Humans
Immunity, Innate / drug effects
Interleukin-8 / metabolism
JNK Mitogen-Activated Protein Kinases*
Lung / drug effects*
Lung / enzymology
Lung / immunology*
MAP Kinase Kinase 4
Metalloproteases / metabolism
Metalloproteases / physiology
Mitogen-Activated Protein Kinase 1 / metabolism
Mitogen-Activated Protein Kinase 1 / physiology
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinase Kinases / metabolism
Mitogen-Activated Protein Kinases / metabolism
Mitogen-Activated Protein Kinases / physiology
Molecular Sequence Data
Respiratory Mucosa / drug effects*
Respiratory Mucosa / enzymology
Respiratory Mucosa / immunology*
Transcriptional Activation / drug effects*
Transcriptional Activation / immunology
Up-Regulation / drug effects
p38 Mitogen-Activated Protein Kinases

Substances

Antimicrobial Cationic Peptides
Cathelicidins
Interleukin-8
ErbB Receptors
JNK Mitogen-Activated Protein Kinases
Mitogen-Activated Protein Kinase 1
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinases
p38 Mitogen-Activated Protein Kinases
MAP Kinase Kinase 4
Mitogen-Activated Protein Kinase Kinases
Metalloproteases