Evaluation of the Ability of LL-37 to Neutralise LPS In Vitro and Ex Vivo

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Title: Evaluation of the Ability of LL-37 to Neutralise LPS In Vitro and Ex Vivo
Authors: Scott, A
Weldon, S
Buchanan, PJ
Schock, B
Ernst, RK
McAuley, DF
Tunney, MM
Irwin, CR
Elborn, JS
Taggart, CC
Item Type: Journal Article
Abstract: BACKGROUND: Human cathelicidin LL-37 is a cationic antimicrobial peptide (AMP) which possesses a variety of activities including the ability to neutralise endotoxin. In this study, we investigated the role of LPS neutralisation in mediating LL-37's ability to inhibit Pseudomonas aeruginosa LPS signalling in human monocytic cells. METHODOLOGY/PRINCIPAL FINDINGS: Pre-treatment of monocytes with LL-37 significantly inhibited LPS-induced IL-8 production and the signalling pathway of associated transcription factors such as NF-κB. However, upon removal of LL-37 from the media prior to LPS stimulation, these inhibitory effects were abolished. These findings suggest that the ability of LL-37 to inhibit LPS signalling is largely dependent on extracellular LPS neutralisation. In addition, LL-37 potently inhibited cytokine production induced by LPS extracted from P. aeruginosa isolated from the lungs of cystic fibrosis (CF) patients. In the CF lung, polyanionic molecules such as glycosaminoglycans (GAGs) and DNA bind LL-37 and impact negatively on its antibacterial activity. In order to determine whether such interactions interfere with the LPS neutralising ability of LL-37, the status of LL-37 and its ability to bind LPS in CF sputum were investigated. Overall our findings suggest that in the CF lung, the ability of LL-37 to bind LPS and inhibit LPS-induced IL-8 production is attenuated as a result of binding to DNA and GAGs. However, LL-37 levels and its concomitant LPS-binding activity can be increased with a combination of DNase and GAG lyase (heparinase II) treatment. CONCLUSIONS/SIGNIFICANCE: Overall, these findings suggest that a deficiency in available LL-37 in the CF lung may contribute to greater LPS-induced inflammation during CF lung disease.
Issue Date: 18-Oct-2011
Date of Acceptance: 28-Sep-2011
URI: http://hdl.handle.net/10044/1/41962
DOI: http://dx.doi.org/10.1371/journal.pone.0026525
ISSN: 1932-6203
Publisher: Public Library of Science
Journal / Book Title: PLOS One
Volume: 6
Issue: 10
Copyright Statement: © 2011 Scott et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keywords: Anti-Inflammatory Agents
Antimicrobial Cationic Peptides
Antitoxins
Cell Line, Tumor
Cystic Fibrosis
DNA
Glycosaminoglycans
Humans
Interleukin-8
Lipopolysaccharides
Lung
Monocytes
Pseudomonas aeruginosa
Signal Transduction
General Science & Technology
MD Multidisciplinary
Publication Status: Published
Article Number: e26525
Appears in Collections:National Heart and Lung Institute
Faculty of Medicine



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