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The Human Cathelicidin LL-37 Preferentially Promotes Apoptosis of Infected Airway Epithelium

Barlow, Peter G.; Beaumont, Paula E.; Cosseau, Celine; Mackellar, Annie; Wilkinson, Thomas S.; Hancock, Robert E. W.; Haslett, Chris; Govan, John R. W.; Simpson, A. John; Davidson, Donald J.

Authors

Paula E. Beaumont

Celine Cosseau

Annie Mackellar

Thomas S. Wilkinson

Robert E. W. Hancock

Chris Haslett

John R. W. Govan

A. John Simpson

Donald J. Davidson



Abstract

Cationic host defense peptides are key, evolutionarily conserved components of the innate immune system. The human cathelicidin LL-37 is an important cationic host defense peptide up-regulated in infection and inflammation, specifically in the human lung, and was shown to enhance the pulmonary clearance of the opportunistic pathogen Pseudomonas aeruginosa in vivo by as yet undefined mechanisms. In addition to its direct microbicidal potential, LL-37 can modulate inflammation and immune mechanisms in host defense against infection, including the capacity to modulate cell death pathways. We demonstrate that at physiologically relevant concentrations of LL-37, this peptide preferentially promoted the apoptosis of infected airway epithelium, via enhanced LL-37-induced mitochondrial membrane depolarization and release of cytochrome c, with activation of caspase-9 and caspase-3 and induction of apoptosis, which only occurred in the presence of both peptide and bacteria, but not with either stimulus alone. This synergistic induction of apoptosis in infected cells was caspase-dependent, contrasting with the caspase-independent cell death induced by supraphysiologic levels of peptide alone. We demonstrate that the synergistic induction of apoptosis by LL-37 and Pseudomonas aeruginosa required specific bacteria-epithelial cell interactions with whole, live bacteria, and bacterial invasion of the epithelial cell. We propose that the LL-37-mediated apoptosis of infected, compromised airway epithelial cells may represent a novel inflammomodulatory role for this peptide in innate host defense, promoting the clearance of respiratory pathogens.

Journal Article Type Article
Acceptance Date Dec 21, 2009
Online Publication Date Dec 1, 2010
Publication Date 2010-12
Deposit Date Mar 27, 2012
Publicly Available Date Jul 13, 2018
Journal American Journal of Respiratory Cell and Molecular Biology
Print ISSN 1044-1549
Electronic ISSN 1535-4989
Publisher American Thoracic Society
Peer Reviewed Peer Reviewed
Volume 43
Issue 6
Pages 692-702
DOI https://doi.org/10.1165/rcmb.2009-0250oc
Keywords Clinical Biochemistry; Cell Biology; Molecular Biology; Pulmonary and Respiratory Medicine
Public URL http://researchrepository.napier.ac.uk/id/eprint/5174
Publisher URL http://dx.doi.org/10.1165/rcmb.2009-0250OC
Contract Date Jul 13, 2018

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