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.

Structure-Function Relationships among Human Cathelicidin Peptides: Dissociation of Antimicrobial Properties from Host Immunostimulatory Activities

“…Similarly, FPRL-1 expression was not seen in cultured keratinocytes or in whole skin by immunostaining. This result agrees with recent studies demonstrating that FPRL-1 is not involved in LL-37-induced activation of epithelial cells (21) or monocytes (23).…”

“…The chemotactic property of LL-37 has been associated with binding via formyl peptide receptor-like 1 (FPRL-1) 2 (19), which belongs to the G i protein-coupled receptor family. Other host cell activities appear to be independent of FPRL-1 and can involve upstream activation of P2X7 or epidermal growth factor receptors (EGFR) (20,21).…”

Antimicrobial protein hCAP18/LL‐37 is highly expressed in breast cancer and is a putative growth factor for epithelial cells

“…In a recent study, it was suggested that LL-37 activates airway epithelial cells by activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK kinase ϭ MEK) via transactivation of the epidermal growth factor receptor (EGFR). 37 However, in our experiments, we did not detect any significant activation of ERK1/2.…”

Cathelicidins in inflammation and tissue repair: Potential therapeutic applications for gastrointestinal disorders

“…LL-37 also induces secretion of interleukin (IL)-8 in airway epithelial cells, leading to increased infiltration of neutrophils and amplification of inflammatory signal. The activation of epithelial cells has been suggested to be mediated through a sequential activation of molecular events, including induction of matrix metalloproteinases (MMP) activities, cleavage of membrane-anchored ligands of epidermal growth factor receptor (EGFR), and the subsequent transactivation of EGFR by these ligands [17] . In vivo study further suggests that this peptide stimulates macrophages to produce chemokines which in turn chemoattract additional cells to the inflamed sites [18] .…”