The antimicrobial peptide cathelicidin enhances activation of lung epithelial cells by LPS

Abstract

ABSTRACT Epithelial cells (ECs) are usually hypore‐sponsive 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 re‐ceptor‐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 catheli‐cidin 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 lyso‐somes. 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 inter‐nalization 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, R., Sierigk, J., Herr, C., Krasteva, G., Kummer, W., Bals, R. The antimicrobial peptide cathelicidin enhances activation of lung epithelial cells by LPS. FASEB J. 24, 4756–4766 (2010). www.fasebj.org