The antimicrobial peptide cathelicidin enhances activation of lung epithelial cells by LPS.
Epithelial cells (ECs) are usually hyporesponsive to various microbial products. Detection of lipopolysaccharide (LPS), the major component of gram-negative bacteria, is impeded, at least in part, by intracellular sequestration of its receptor, Toll-like receptor-4 (TLR4). In this study, using human bronchial ECs (hBECs) as a model of mucosal epithelium, we tested the hypothesis that the human LPS-binding, membrane-active cationic host defense peptide cathelicidin LL-37 augments epithelial response to LPS by facilitating its delivery to TLR4-containing intracellular compartments. We found that LL-37 significantly increases uptake of LPS by ECs with subsequent targeting to cholera toxin subunit B-labeled structures and lysosomes. This uptake is peptide specific, dose and time dependent, and involves the endocytotic machinery, functional lipid rafts, and epidermal growth factor receptor signaling. Cathelicidin-dependent LPS internalization resulted in significant increased release of the inflammatory cytokines IL-6 and IL-8. This indicates that, in ECs, this peptide may replace LPS-binding protein functions. In polarized ECs, the effect of LL-37 was restricted to the basolateral compartment of the epithelial membrane, suggesting that LL-37-mediated activation of ECs by LPS may be relevant to disease conditions associated with damage to the epithelial barrier. In summary, our study identified a novel role of LL-37 in host-microbe interactions as a host factor that licenses mucosal ECs to respond to LPS.
Shaykhiev
Renat
R
University Hospital Giessen and Marburg, Department of Internal Medicine, Division of Pulmonology, Universities of Giessen and Marburg Lung Center, Philipps University Marburg, Marburg, Germany.
Sierigk
Johannes
J
Herr
Christian
C
Krasteva
Gabriela
G
Kummer
Wolfgang
W
Bals
Robert
R
D023181:Antimicrobial Cationic Peptides; D001692:Biological Transport / Q000187:drug effects; D054804:Cathelicidins / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D004705:Endocytosis / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D008070:Lipopolysaccharides / Q000378:metabolism* / Q000494:pharmacology*; D008168:Lung / Q000166:cytology*; D018613:Microscopy, Confocal; D015398:Signal Transduction / Q000187:drug effects
D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D008070:Lipopolysaccharides; C512478:EGFR protein, human; D066246:ErbB Receptors