title: The antimicrobial peptide cathelicidin enhances activation of lung epithelial cells by LPS.
abstract: 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.
authors.affiliation: University Hospital Giessen and Marburg, Department of Internal Medicine, Division of Pulmonology, Universities of Giessen and Marburg Lung Center, Philipps University Marburg, Marburg, Germany.
authors.forename: Renat
authors.initials: R
authors.lastname: Shaykhiev
authors.forename: Johannes
authors.initials: J
authors.lastname: Sierigk
authors.forename: Christian
authors.initials: C
authors.lastname: Herr
authors.forename: Gabriela
authors.initials: G
authors.lastname: Krasteva
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kummer
authors.forename: Robert
authors.initials: R
authors.lastname: Bals
mesh_terms: 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
chemical_list: D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D008070:Lipopolysaccharides; C512478:EGFR protein, human; D066246:ErbB Receptors