Cathelicidin LL-37 and the Defensins: The Body’s Own Antimicrobial Peptides

Innate immunity

Cathelicidin LL-37 and the defensins are the body’s own antimicrobial peptides: short, positively charged molecules made by white blood cells and by the epithelial tissues that line skin, airways and gut. They kill or disable microbes, but they also signal to the immune system, and when they are out of balance they have been linked to inflammatory disease.

What are host-defense peptides?

Host-defense peptides (also called antimicrobial peptides) are part of innate immunity, the fast, non-specific first line of defense. Humans make two major families: the single human cathelicidin, LL-37, and the defensins. For the wider family of antimicrobial peptides, including those from other species, see our antimicrobial peptides explainer; this article focuses on the two human families.

Cathelicidin LL-37: from precursor to peptide

LL-37 is encoded by the CAMP gene. The gene product is a 170-residue precursor (hCAP18) whose signal peptide covers residues 1 to 30, followed by a cathelin-like propeptide (residues 31 to 131) with no antimicrobial activity of its own. LL-37 is the 37 residues at the C-terminal end, residues 134 to 170 in UniProt, and begins with two leucines, hence the name. It is released when proteinase 3 cleaves the precursor outside the cell. UniProt also lists shorter processed forms such as FALL-39, LL-29, LL-23, KS-30 and KR-20.

Counting from its sequence (LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVPRTES), LL-37 carries 11 lysine and arginine residues against 5 aspartate and glutamate residues, a net positive charge of roughly +6 and a mass near 4.5 kDa. That positive charge is typical of antimicrobial peptides, which are drawn to the negatively charged surfaces of bacteria. UniProt reports that LL-37 forms pores in membranes in vitro, is active against Gram-negative and Gram-positive bacteria, and binds lipopolysaccharide (LPS). Its tissue sources include neutrophils and bone marrow, and eccrine sweat on skin.

Vitamin D and the CAMP gene

In 2004 and 2005, two groups showed that the vitamin D receptor binds response elements in the CAMP gene, and that 1,25-dihydroxyvitamin D3 raised its expression in keratinocytes, monocytes and neutrophils. The response element is conserved in primates but absent in mouse, rat and dog, which helps explain why mouse models do not always mirror human cathelicidin biology. These are gene-regulation findings and not evidence that any supplement changes infection risk.

The defensins

Defensins are small cysteine-rich peptides held in a compact fold by three internal disulfide bonds. Humans have two functional families, distinguished by how the six cysteines pair up. In alpha-defensins the pairing is C1-C6, C2-C4 and C3-C5; in beta-defensins it is C1-C5, C2-C4 and C3-C6.

Alpha-defensins HNP-1 to HNP-4 are stored in neutrophil granules, while HD5 and HD6 are made by Paneth cells in the small intestine. Beta-defensins are produced by epithelial cells and leukocytes in skin, airways and other surfaces. A third family, the theta-defensins, exists in rhesus macaques and baboons, but the human gene carries a premature stop codon and is a pseudogene. Defensin mechanisms range from disrupting microbial membranes to interfering with microbial metabolism, and some also signal to immune cells; UniProt notes that human beta-defensin 2 acts as a ligand for the chemokine receptor CCR6, attracting immature dendritic cells and memory T cells. See our GDF15 article for another example of a stress-responsive signaling protein, and our half-life explainer for why peptides in general are cleared quickly.

Reported roles in disease research

Crohn’s disease. A 2005 PNAS study found reduced Paneth-cell HD5 and HD6 and lower antibacterial activity in mucosal extracts from people with ileal Crohn’s disease, but not in colonic Crohn’s disease or ulcerative colitis, and the reduction did not track inflammation severity. The authors proposed, rather than proved, that this defensin deficiency may contribute to disease.

Psoriasis. A 2007 Nature paper reported that LL-37 binds self-DNA, forming aggregates that are retained in endosomes of plasmacytoid dendritic cells and trigger TLR9, and identified LL-37 as the key activator of these cells in psoriasis.

Rosacea. A 2007 Nature Medicine paper reported that rosacea skin has increased cathelicidin, processed into different peptide forms, together with higher activity of the protease KLK5 (SCTE). In mice, these peptide forms or the protease were enough to cause skin inflammation.

What the human evidence shows

There is no approved LL-37 medicine that we could find. The main clinical report is a first-in-human randomized, placebo-controlled trial (Grönberg et al., 2014) of topical LL-37 in 34 people with hard-to-heal venous leg ulcers. Only the lowest of three tested concentrations produced a statistically significant benefit (a 68% mean reduction in ulcer area, p=0.003), the middle dose did not reach significance, and the highest dose looked no different from placebo; no safety concerns were identified. A small trial with this unusual dose-response shape is a starting point for further study, not proof of an effective treatment.

Cautions and considerations

Synthetic LL-37 and other research peptides are not approved medicines, and purity and identity are not assured. Nothing here is guidance for human use. For lab-math context only, see the reconstitution calculator and peptide degradation.

Frequently asked questions

Is LL-37 an antibiotic?

It kills microbes in laboratory tests, but in the body it is better understood as part of immune signaling. No LL-37 product is approved as an antibiotic.

What is the difference between LL-37 and defensins?

LL-37 is a single linear peptide cut from the cathelicidin precursor; defensins are a family of folded, disulfide-bonded peptides with a different structure and gene origin.

Why does the human cathelicidin have only one form?

Humans have a single cathelicidin gene, CAMP, although proteolytic processing creates shorter fragments. Other species carry several cathelicidin genes.

Are defensins and LL-37 related to the peptide hormones?

They share size and chemistry, but they act locally in tissues. See oxytocin for a classic peptide hormone by comparison.

References

1. UniProt P49913 — Cathelicidin antimicrobial peptide (CAMP), human
2. UniProt O15263 — Beta-defensin 4A (hBD-2), human; and UniProt P12838 — Neutrophil defensin 4 (HNP-4)
3. Wang TT et al. Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J Immunol 2004;173:2909-2912
4. Gombart AF et al. Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1,25-dihydroxyvitamin D3. FASEB J 2005;19:1067-1077
5. Wehkamp J et al. Reduced Paneth cell alpha-defensins in ileal Crohn’s disease. PNAS 2005;102:18129-18134
6. Lande R et al. Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature 2007;449:564-569
7. Yamasaki K et al. Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea. Nat Med 2007;13:975-980
8. Grönberg A et al. Treatment with LL-37 is safe and effective in enhancing healing of hard-to-heal venous leg ulcers: a randomized, placebo-controlled clinical trial. Wound Repair Regen 2014;22:613-621

Informational only — not medical advice. This article is for educational purposes. It does not recommend, sell or instruct personal human use of any compound. Consult a qualified healthcare professional for any health decision. Content is intended for adults 21+. Verify scientific details against the primary sources cited.