An angiogenic role for the human peptide antibiotic LL-37/hCAP-18

Abstract

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

Antimicrobial protein hCAP18/LL‐37 is highly expressed in breast cancer and is a putative growth factor for epithelial cells

“…These findings clearly contrast with the hypothesized antitumor effect that has been proposed for antimicrobial peptides, but are consistent with recent findings that suggest a role for hCAP18/LL-37 in epithelial repair and angiogenesis. 5,10 Further supporting hCAP18/LL-37 as a growth-promoting factor, we here demonstrate that proliferation of epithelial cells was significantly enhanced both by treatment with synthetic biologically active LL-37 peptide and by transgenic expression of hCAP18.…”

“…The G-protein-coupled receptor FPRL1 has been shown to mediate LL-37-induced effects in eukaryote cells; 4,5 to assess its potential role in the present setting, we investigated the expression of FPRL1 protein in mammary tissue and found strong immunoreactivity for FPRL1 both in breast cancer cells and in normal glandular epithelium (Fig. 5a and b).…”

“…1,2 Extracellular proteolytic processing of the holoprotein releases the LL-37 peptide, which has broad antimicrobial activity 1,3 as well as effects on host cells mediated by the G-protein-coupled receptor, formyl peptide receptor-like 1 (FPRL1). 4,5 hCAP18 is present in leucocytes 6 and is expressed in skin and other epithelia, where it is upregulated in association with inflammation 7,8 and injury, 9,10 consistent with a role in innate barrier protection. Recently, antimicrobial proteins including cathelicidins have been proposed to play a role also in the nonspecific host defense against tumors.…”

Transient cutaneous adenoviral gene therapy with human host defense peptide hCAP-18/LL-37 is effective for the treatment of burn wound infections

“…Still, LL-37 was not as effective as, for example, HBD 2 or 3 shown in many in vitro studies. However, LL-37 has a broader spectrum concerning the antimicrobial activity and is moreover able to induce neovascularization 15 and to demonstrate binding of bacterial endotoxin (LPS, minimal active concentration: 12.5 mg/ml) 14 or chemotactic activity for neutrophils, monocytes 33 and mast cells (effective concentration 1-10 mM). 32,34 Finally, regarding the actual resistance problem of classic antibiotics and its rapid progress, it must be mentioned that there is only a very low tendency of developing resistance to HDP.…”

“…It has been recently demonstrated that LL-37 performs a central role in linking the innate immune response and the inflammation with angiogenesis. 15 Owing to the loss of the mechanical barrier of the skin in burn injury and the locally reduced expression of HDP, patients are prone to bacterial colonization and wound infection. 14,[16][17][18] In addition, a deficiency of hCAP-18/LL-37 in the skin of patients with atopic dermatitis may predestine an increased risk for skin infections.…”