An angiogenic role for the human peptide antibiotic LL-37/hCAP-18.
Antimicrobial peptides are effector molecules of the innate immune system and contribute to host defense and regulation of inflammation. The human cathelicidin antimicrobial peptide LL-37/hCAP-18 is expressed in leukocytes and epithelial cells and secreted into wound and airway surface fluid. Here we show that LL-37 induces angiogenesis mediated by formyl peptide receptor-like 1 expressed on endothelial cells. Application of LL-37 resulted in neovascularization in the chorioallantoic membrane assay and in a rabbit model of hind-limb ischemia. The peptide directly activates endothelial cells, resulting in increased proliferation and formation of vessel-like structures in cultivated endothelial cells. Decreased vascularization during wound repair in mice deficient for CRAMP, the murine homologue of LL-37/hCAP-18, shows that cathelicidin-mediated angiogenesis is important for cutaneous wound neovascularization in vivo. Taken together, these findings demonstrate that LL-37/hCAP-18 is a multifunctional antimicrobial peptide with a central role in innate immunity by linking host defense and inflammation with angiogenesis and arteriogenesis.
Koczulla
Rembert
R
Hospital of the University of Marburg, Department of Internal Medicine, Philipps Universtät Marburg, Marburg, Germany.
von Degenfeld
Georges
G
Kupatt
Christian
C
Krötz
Florian
F
Zahler
Stefan
S
Gloe
Torsten
T
Issbrücker
Katja
K
Unterberger
Pia
P
Zaiou
Mohamed
M
Lebherz
Corinna
C
Karl
Alexander
A
Raake
Philip
P
Pfosser
Achim
A
Boekstegers
Peter
P
Welsch
Ulrich
U
Hiemstra
Pieter S
PS
Vogelmeier
Claus
C
Gallo
Richard L
RL
Clauss
Matthias
M
Bals
Robert
R
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry*; D023181:Antimicrobial Cationic Peptides / Q000235:genetics / Q000494:pharmacology*; D017209:Apoptosis; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D054804:Cathelicidins; D002455:Cell Division; D002478:Cells, Cultured; D003094:Collagen / Q000494:pharmacology; D006224:Cricetinae; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism; D007511:Ischemia; D007797:Laminin / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D008647:Mesocricetus; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D018919:Neovascularization, Physiologic; D010455:Peptides / Q000737:chemistry; D011355:Prodrugs / Q000494:pharmacology*; D011509:Proteoglycans / Q000494:pharmacology; D011817:Rabbits; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014945:Wound Healing
D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D054804:Cathelicidins; D004338:Drug Combinations; D004791:Enzyme Inhibitors; C105101:FPR2 protein, human; D007211:Indoles; D007797:Laminin; D008301:Maleimides; D016328:NF-kappa B; D010455:Peptides; D011355:Prodrugs; D011509:Proteoglycans; D011956:Receptors, Cell Surface; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; C059485:matrigel; D003094:Collagen; C070515:bisindolylmaleimide I; D002118:Calcium; D000111:Acetylcysteine