title: The antimicrobial peptide LL-37 activates innate immunity at the airway epithelial surface by transactivation of the epidermal growth factor receptor.
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.
authors.affiliation: Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands. G.S.Tjabringa@LUMC.nl
authors.forename: G Sandra
authors.initials: GS
authors.lastname: Tjabringa
authors.forename: Jamil
authors.initials: J
authors.lastname: Aarbiou
authors.forename: Dennis K
authors.initials: DK
authors.lastname: Ninaber
authors.forename: Jan Wouter
authors.initials: JW
authors.lastname: Drijfhout
authors.forename: Ole E
authors.initials: OE
authors.lastname: Sørensen
authors.forename: Niels
authors.initials: N
authors.lastname: Borregaard
authors.forename: Klaus F
authors.initials: KF
authors.lastname: Rabe
authors.forename: Pieter S
authors.initials: PS
authors.lastname: Hiemstra
mesh_terms: 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
chemical_list: 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