The human cationic host defense peptide LL-37 mediates contrasting effects on apoptotic pathways in different primary cells of the innate immune system.
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 P2X(7) 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.
Barlow
Peter G
PG
MRC/University of Edinburgh Centre for Inflammation Research, Queen's Medical Research Institute, W2.03, 47 Little France Crescent, Edinburgh EH16 4TJ, Scotland.
Li
Yuexin
Y
Wilkinson
Thomas S
TS
Bowdish
Dawn M E
DM
Lau
Y Elaine
YE
Cosseau
Celine
C
Haslett
Christopher
C
Simpson
A John
AJ
Hancock
Robert E W
RE
Davidson
Donald J
DJ
D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology / Q000502:physiology*; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000187:drug effects / Q000276:immunology; D053148:Caspase 3 / Q000187:drug effects / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000187:drug effects; D004306:Dose-Response Relationship, Immunologic; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D054804:Cathelicidins
D023181:Antimicrobial Cationic Peptides; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D016207:Cytokines; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D053148:Caspase 3; D054804:Cathelicidins