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Published online before print June 22, 2006
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,1,2
* MRC/University of Edinburgh Centre for Inflammation Research, Queen’s Medical Research Institute, Scotland; and
Department of Microbiology and Immunology, University of British Columbia, Vancouver, Canada
3 Correspondence: MRC/University of Edinburgh Centre for Inflammation Research, Queen’s Medical Research Institute, W2.03, 47 Little France Crescent, Edinburgh EH16 4TJ, Scotland. E-mail: Donald.Davidson{at}ed.ac.uk
ABSTRACT
The human cathelicidin LL-37 is a cationic host defense peptide (antimicrobial peptide) expressed primarily by neutrophils and epithelial cells. This peptide, up-regulated under conditions of inflammation, has immunomodulatory and antimicrobial functions. We demonstrate that LL-37 is a potent inhibitor of human neutrophil apoptosis, signaling through P2X7 receptors and G-protein-coupled receptors other than the formyl peptide receptor-like-1 molecule. This process involved modulation of Mcl-1 expression, inhibition of BID and procaspase-3 cleavage, and the activation of phosphatidylinositol-3 kinase but not the extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase pathway. In contrast to the inhibition of neutrophil apoptosis, LL-37 induced apoptosis in primary airway epithelial cells, demonstrating alternate consequences of LL-37-mediated modulation of apoptotic pathways in different human primary cells. We propose that these novel immunomodulatory properties of LL-37 contribute to peptide-mediated enhancement of innate host defenses against acute infection and are of considerable significance in the development of such peptides and their synthetic analogs as potential therapeutics for use against multiple antibiotic-resistant infectious diseases.
Key Words: cathelicidin • antimicrobial peptide • neutrophil • epithelial cell • FPRL-1 • P2X7
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