LL-37

LL-37 is the sole human cathelicidin antimicrobial peptide — the C-terminal 37 amino acid fragment of the hCAP18 precursor protein (encoded by the CAMP gene), released by proteinase 3 cleavage from neutrophil granules upon degranulation and by kallikreins (KLK5, KLK7) in skin. Produced by neutrophils, macrophages, mast cells, NK cells, and epithelial cells of skin, lung, and intestine, LL-37 functions both as a direct antimicrobial agent and as a multifunctional immunomodulatory signalling peptide.

LL-37 expression is strongly induced by 1,25-dihydroxyvitamin D3 through vitamin D response elements in the CAMP gene promoter — one of the mechanisms connecting vitamin D status to innate immune capacity. Toll-like receptor activation by bacterial PAMPs (LPS via TLR4, lipoteichoic acid via TLR2, flagellin via TLR5) also induces LL-37 expression through NFkB and IRF3 signalling, providing a feed-forward amplification of the innate immune response: bacterial recognition drives production of the peptide that directly kills bacteria.

The antimicrobial mechanism involves direct bacterial membrane disruption. LL-37 adopts an amphipathic alpha-helical conformation in lipid environments — a helix with hydrophobic residues concentrated on one face and cationic Arg and Lys residues on the other. This amphipathic helix inserts into the negatively charged outer membranes of bacteria (rich in phosphatidylglycerol, cardiolipin, and LPS), disrupting membrane integrity through toroidal pore formation or carpet-model solubilisation. Selectivity for bacterial over mammalian membranes is conferred by membrane charge: bacterial outer leaflets are anionic and attract cationic LL-37, while mammalian outer leaflets are predominantly zwitterionic (phosphatidylcholine, sphingomyelin) and resist LL-37 insertion at concentrations below approximately 10-20 microM.

LL-37 interacts with multiple cell-surface receptors to produce immunomodulatory effects beyond direct killing. FPRL1 (FPR2/ALX, Gi-coupled GPCR) activation promotes chemotaxis of neutrophils, monocytes, and T cells. P2X7 receptor activation at higher concentrations triggers NLRP3 inflammasome assembly and IL-1beta processing. EGFR transactivation in keratinocytes drives proliferation and migration through MAPK/ERK signalling. Direct binding to extracellular double-stranded DNA and RNA enables LL-37 to deliver nucleic acids to endosomal TLR7, TLR8, and TLR9, amplifying innate immune nucleic acid sensing.

LL-37 adopts distinct roles at wound sites: it is chemotactic for keratinocytes, promotes re-epithelialisation through EGFR signalling, stimulates angiogenesis through VEGF induction, and modulates macrophage polarisation from M1 pro-inflammatory to M2 pro-resolving phenotypes during the resolution phase. These wound healing biology connections make LL-37 research complementary to BPC-157, TB-500, and GHK-Cu studies — addressing antimicrobial and immune cell coordination aspects of tissue repair that the other compounds do not cover.

Research applications: minimum inhibitory concentration (MIC) determination against gram-positive (S. aureus, S. epidermidis) and gram-negative (E. coli, P. aeruginosa) reference strains; membrane permeabilisation assays (SYTOX green propidium iodide uptake, ONPG hydrolysis as inner membrane integrity measure); biofilm disruption studies; FPRL1 calcium mobilisation and chemotaxis assays; keratinocyte scratch assay migration with EGFR inhibitor controls; and Matrigel tube formation with anti-VEGF controls.

MW: 4493.33 g/mol. CAS: 154947-66-7. Amphipathic — prone to aggregation during freeze-thaw; aliquot single-use volumes. Reconstitute in sterile water at 1mg/mL. Store lyophilised at -20°C. For laboratory and analytical research purposes only.

LL-37 aggregation note: as an amphipathic peptide, LL-37 has a tendency to self-aggregate, particularly at higher concentrations (above approximately 5uM) and at neutral to alkaline pH. Aggregated LL-37 shows reduced biological activity. To minimise aggregation: dissolve in sterile water first, then dilute to working concentrations immediately before addition to cells; avoid freeze-thaw cycles of reconstituted stock (aliquot single-use volumes); and prepare fresh working dilutions daily for experiments spanning multiple days. For antimicrobial MIC assays, use Mueller-Hinton broth and confirm peptide activity with positive control (gentamicin, ampicillin). MW: 4493.33 g/mol. Reconstitute in sterile water at 1mg/mL. Store lyophilised at -20°C. For laboratory and analytical research purposes only.