Structure-function relationships among human cathelicidin peptides: dissociation of antimicrobial properties from host immunostimulatory activities.
Cathelicidins and other antimicrobial peptides are deployed at epithelial surfaces to defend against infection. These molecules have broad-spectrum killing activity against microbes and can have effects on specific mammalian cell types, potentially stimulating additional immune defense through direct chemotactic activity or induction of cytokine release. In humans, the cathelicidin hCAP18/LL-37 is processed to LL-37 in neutrophils, but on skin it can be further proteolytically processed to shorter forms. The influence of these cathelicidin peptides on keratinocyte function is not known. In the current study, DNA microarray analysis and confirmatory protein analysis showed that LL-37 affects the expression of several chemokines and cytokines by keratinocytes. Analysis of a synthetic peptide library derived from LL-37 showed that antimicrobial activity against bacterial, fungal, and viral skin pathogens resides within specific domains of the parent peptide, but antimicrobial activity does not directly correlate with the ability to stimulate IL-8 production in keratinocytes. IL-8 release was induced by d- and l-amino acid forms of cathelicidin and correlated with membrane permeability, suggesting that highly structure-specific binding to a cell surface receptor is not likely. However, this effect was inhibited by either pertussis toxin or AG1478, an epidermal growth factor receptor tyrosine kinase inhibitor, suggesting that cathelicidin may indirectly stimulate multiple signaling pathways associated with cell surface receptors. Taken together, these observations suggest that proteolytic processing may alter the balance between cathelicidin antimicrobial and host immunostimulatory functions.
Braff
Marissa H
MH
Division of Dermatology, University of California, and Veterans Affairs San Diego Healthcare Center, San Diego, CA 92161, USA.
Hawkins
Mi'i A
MA
Di Nardo
Anna
A
Lopez-Garcia
Belen
B
Howell
Michael D
MD
Wong
Cathy
C
Lin
Kenneth
K
Streib
Joanne E
JE
Dorschner
Robert
R
Leung
Donald Y M
DY
Gallo
Richard L
RL
D023181:Antimicrobial Cationic Peptides / Q000737:chemistry / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects; D002176:Candida albicans / Q000187:drug effects; D002463:Cell Membrane Permeability; D018925:Chemokines / Q000235:genetics; D016207:Cytokines / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007109:Immunity; D007231:Infant, Newborn; D016209:Interleukin-8 / Q000096:biosynthesis / Q000378:metabolism; D015603:Keratinocytes / Q000276:immunology*; D020411:Oligonucleotide Array Sequence Analysis; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology; D019151:Peptide Library; D013329:Structure-Activity Relationship; D014780:Viruses / Q000187:drug effects; D054804:Cathelicidins
D023181:Antimicrobial Cationic Peptides; D018925:Chemokines; D016207:Cytokines; D016209:Interleukin-8; D010446:Peptide Fragments; D019151:Peptide Library; D054804:Cathelicidins