LL-37 5 MG

Description

LL-37 is the only known human cathelicidin, a member of a broad family of peptides known as antimicrobial peptides (AMPs). Primarily produced by macrophages and polymorphonuclear leukocytes—both types of white blood cells—LL-37 plays a vital role in the body’s innate immune response by targeting and neutralizing harmful bacteria.

Beyond its antimicrobial function, LL-37 has been studied for its involvement in a range of biological processes. Research suggests it may influence autoimmune activity, contribute to wound healing, and play a role in certain cancer-related mechanisms. These diverse functions have made LL-37 a subject of increasing interest in immunology and regenerative medicine.

LL-37 Structure

Source: PubChem

Sequence: -Leu-Leu-Gly-Asp-Phe-Phe-Arg-Lys-Ser-Lys-Glu-Lys-Ile-Gly-Lys-Glu-Phe-Lys-Arg-Ile-Val-Gln-Arg-Ile-Lys-Asp-Phe-Leu-Arg-Asn-Leu-Val-Pro-Arg-Thr-Glu-Ser
Molecular Formula: C₂₀₅H₃₄₀N₆₀O₅₃
vMolecular Weight: 4493.342 g/mol
PubChem CID: 16198951
vCAS Number: 154947-66-7
Synonyms: CAP-18, Cathelicidin, antibacterial peptide LL-37

LL-37 Research

LL-37 and Inflammatory Diseases

Although LL-37 is best known as an antimicrobial peptide, research has shown it also plays a significant role in various inflammatory and autoimmune conditions, including psoriasis, lupus, rheumatoid arthritis, and atherosclerosis. Its effects on the immune system are context-dependent, varying according to the local inflammatory environment and the cell types involved.

LL-37 has been observed to:

• Decrease keratinocyte apoptosis
• Increase interferon-alpha (IFN-α) production
• Alter chemotaxis of neutrophils and eosinophils
• Downregulate signaling through Toll-like receptor 4 (TLR4)
• Increase interleukin-18 (IL-18) production
• Reduce the formation of atherosclerotic plaques [1]

Notably, LL-37 does not exert the same immune effects in all situations. Cell culture studies have demonstrated that the surrounding inflammatory environment influences how immune cells respond to LL-37. For example, T-cells tend to increase their inflammatory response to LL-37 when in a resting state, but exhibit reduced inflammation when already activated [2].

These findings suggest that LL-37 may serve a homeostatic function—helping to modulate and balance immune responses, particularly during infections. This regulatory behavior points to its potential role in controlling excessive inflammation seen in autoimmune diseases. While LL-37 was once thought to contribute to autoimmune pathology, newer evidence indicates that elevated LL-37 levels in these conditions may actually act to mitigate more severe inflammation.

Source: Karger

LL-37: A Potent Antimicrobial Peptide

LL-37 is a key component of the innate immune system and one of the first responders to infection. Under normal conditions, LL-37 is present at low levels in the skin, but its concentration increases rapidly in response to invading pathogens. Studies suggest it works synergistically with other antimicrobial proteins, such as human beta-defensin 2, to combat infection [3].

The primary mechanism of LL-37 involves binding to lipopolysaccharide (LPS), a major component of the outer membrane of gram-negative bacteria. LPS is essential for bacterial membrane stability, and by targeting it, LL-37 disrupts bacterial integrity, leading to cell death [4].

Interestingly, LL-37 also exhibits potent activity against gram-positive bacteria. It enhances the effects of lysozyme—an enzyme involved in the destruction of gram-positive organisms like Staphylococcus aureus—making it a potential candidate for treating resistant staph infections [5].

LL-37 and Lung Disease

LPS is not exclusive to bacterial membranes—it can also be aerosolized in environments contaminated with mold or fungi. Inhalation of airborne LPS can lead to inadequate immune responses in lung tissue, contributing to conditions like toxic dust syndrome, asthma, and COPD. Research is underway exploring LL-37 as a potential inhaled therapeutic in such scenarios [6].

Studies also indicate that LL-37 promotes epithelial cell proliferation and wound healing in the lungs. It appears to attract airway epithelial cells to sites of injury, stimulate blood vessel growth, and support tissue regeneration. These findings highlight LL-37’s role as a key homeostatic regulator in pulmonary health [7].

LL-37 in Arthritis

In rheumatoid arthritis models, LL-37 is found in elevated concentrations within affected joints. While initially suspected of contributing to inflammation, recent research suggests LL-37’s presence may be a protective response to inflammation rather than a cause [8].

Evidence supporting this includes:

• LL-37 deficiency does not alter disease outcomes in animal models of arthritis or lupus.
• Its presence in inflamed joints may be an incidental result of immune activation [9].

Moreover, LL-37-derived peptides have demonstrated protective effects by reducing collagen damage and lowering antibody levels against type II collagen in arthritic joints [10]. These peptides also regulate inflammation linked to interleukin-32, a cytokine associated with arthritis severity [11].

Upregulation of Toll-like receptor 3 (TLR3) in synovial fibroblasts may worsen inflammation, and LL-37 has been shown to interact with TLR4 to either promote or suppress inflammation depending on the environment. This context-sensitive behavior may allow LL-37 to selectively reduce pro-inflammatory macrophage activity [12][13].

LL-37 and Gut Health

In the intestinal tract, LL-37 supports epithelial integrity and reduces inflammation. It promotes the migration of barrier-forming cells and limits cell death during inflammatory responses. These actions suggest a potential role for LL-37 in treating inflammatory bowel diseases (IBD), supporting recovery after intestinal surgery, or as an adjuvant to antibiotic therapy to reduce gastrointestinal side effects [14].

LL-37 also works synergistically with human beta-defensin 2 in maintaining intestinal epithelial health and preventing TNF-alpha-induced cell death [15]. Since current TNF-alpha inhibitors, though effective, carry significant risks (e.g., tuberculosis), LL-37-based therapies could offer a safer alternative in managing IBD.

LL-37 and Intestinal Cancer

Research on LL-37’s role in cancer has shown mixed outcomes, but data indicate it may be protective in gastrointestinal and oral cancers, particularly those linked to tobacco use. These effects appear to be mediated via a vitamin D-dependent mechanism, which could explain the observed link between vitamin D levels and reduced GI cancer risk. Vitamin D seems to activate anti-cancer macrophage responses through LL-37 [16].

LL-37 and Angiogenesis

LL-37 stimulates prostaglandin E2 (PGE2) production in endothelial cells, promoting angiogenesis—the growth of new blood vessels [17]. This process is crucial in both health and disease, influencing wound healing, cardiovascular conditions, and cancer. As such, LL-37 serves as a valuable tool in angiogenesis research and a potential therapeutic target for promoting or inhibiting blood vessel formation depending on clinical needs.

Ongoing LL-37 Research

LL-37 continues to attract significant scientific interest due to its unique structural and functional characteristics. Interestingly, the structure of LL-37 in humans differs from that found in other mammals, resulting in functional variations across species [18]. These differences offer valuable insight into how even minor changes in amino acid sequences can influence a peptide’s three-dimensional configuration and receptor interactions. As a result, LL-37 serves as a powerful model for understanding protein folding, receptor specificity, and targeted biochemical design.

Preclinical studies in mice have shown that LL-37 exhibits minimal to moderate side effects, with low oral but excellent subcutaneous bioavailability. However, it’s important to note that dosages used in animal models do not directly translate to human equivalents.

LL-37 available through this site is intended strictly for scientific and educational research. It is not approved for human use or consumption. Purchasers must be qualified researchers or licensed professionals conducting controlled laboratory investigations.

Scientific Acknowledgment

Dr. Daniela Xhindoli, PhD, is a respected researcher at the University of Trieste (UNITS), Department of Life Sciences. Her work focuses on gram-negative bacteria and the biological activities of the LL-37 peptide, particularly its ability to simultaneously modulate pro-inflammatory and anti-inflammatory pathways, as well as its potent antimicrobial properties.

Dr. Xhindoli is recognized as one of the leading scientists contributing to the expanding body of research on LL-37. Her work is cited in reference [18] on this website to acknowledge the scientific rigor and valuable contributions made to the understanding of this complex peptide.

Disclaimer: Dr. Daniela Xhindoli does not endorse, promote, or advocate the purchase, sale, or use of LL-37 for any purpose. There is no affiliation or professional relationship, explicit or implied, between Dr. Xhindoli and Peptide Sciences. The inclusion of her name and research is solely intended to credit the scientific community and its ongoing efforts in peptide research.

References

1. J. M. Kahlenberg and M. J. Kaplan, “Little peptide, big effects: the role of LL-37 in inflammation and autoimmune disease,” J. Immunol. Baltim. Md 1950, vol. 191, no. 10, Nov. 2013.
2. D. S. Alexandre-Ramos et al., “LL-37 treatment on human peripheral blood mononuclear cells modulates immune response and promotes regulatory T-cells generation,” Biomed. Pharmacother. Biomedecine Pharmacother., vol. 108, pp. 1584–1590, Dec. 2018.
3. P. Y. Ong et al., “Endogenous antimicrobial peptides and skin infections in atopic dermatitis,” N. Engl. J. Med., vol. 347, no. 15, pp. 1151–1160, Oct. 2002.
4. C. D. Ciornei, T. Sigurdardóttir, A. Schmidtchen, and M. Bodelsson, “Antimicrobial and chemoattractant activity, lipopolysaccharide neutralization, cytotoxicity, and inhibition by serum of analogs of human cathelicidin LL-37,” Antimicrob. Agents Chemother., vol. 49, no. 7, pp. 2845–2850, Jul. 2005.
5. X. Chen et al., “Synergistic effect of antibacterial agents human β-defensins, cathelicidin LL-37 and lysozyme against Staphylococcus aureus and Escherichia coli,” J. Dermatol. Sci., vol. 40, no. 2, pp. 123–132, Nov. 2005.
6. M. Golec, “Cathelicidin LL-37: LPS-neutralizing, pleiotropic peptide,” Ann. Agric. Environ. Med. AAEM, vol. 14, no. 1, pp. 1–4, 2007.
7. R. Shaykhiev et al., “Human endogenous antibiotic LL-37 stimulates airway epithelial cell proliferation and wound closure,” Am. J. Physiol. Lung Cell. Mol. Physiol., vol. 789, no. 5, pp. L842-848, Nov. 2005.
8. M. H. Hoffmann et al., “The cathelicidins LL-37 and rCRAMP are associated with pathogenic events of arthritis in humans and rats,” Ann. Rheum. Dis., vol. 72, no. 7, pp. 1239–1248, Jul. 2013.
9. D. Kienhöfer et al., “No evidence of pathogenic involvement of cathelicidins in patient cohorts and mouse models of lupus and arthritis,” PloS One, vol. 9, no. 12, p. e115474, 2014.
10. L. N. Y. Chow et al., “Human cathelicidin LL-37-derived peptide IG-19 confers protection in a murine model of collagen-induced arthritis,” Mol. Immunol., vol. 57, no. 2, pp. 86–92, Feb. 2014.
11. K.-Y. G. Choi, S. Napper, and N. Mookherjee, “Human cathelicidin LL-37 and its derivative IG-19 regulate interleukin-32-induced inflammation,” Immunology, vol. 143, no. 1, pp. 68–80, Sep. 2014.
12. W. Zhu et al., “Arthritis is associated with T-cell-induced upregulation of Toll-like receptor 3 on synovial fibroblasts,” Arthritis Res. Ther., vol. 13, no. 3, p. R103, Jun. 2011.
13. K. L. Brown et al., “Host defense peptide LL-37 selectively reduces proinflammatory macrophage responses,” J. Immunol. Baltim. Md 1950, vol. 186, no. 9, pp. 5497–5505, May 2011.
14. J.-M. Otte et al., “Effects of the cathelicidin LL-37 on intestinal epithelial barrier integrity,” Regul. Pept., vol. 156, no. 1–3, pp. 104–117, Aug. 2009.
15. J.-M. Otte et al., “Human beta defensin 2 promotes intestinal wound healing in vitro,” J. Cell. Biochem., vol. 104, no. 6, pp. 2286–2297, Aug. 2008.
16. X. Chen et al., “Roles and Mechanisms of Human Cathelicidin LL-37 in Cancer,” Cell. Physiol. Biochem. Int. J. Exp. Cell. Physiol. Biochem. Pharmacol., vol. 47, no. 3, pp. 1060–1073, 2018.
17. Salvado M. Dolores, Di Gennaro Antonio, Lindbom Lennart, Agerberth Birgitta, and Haeggström Jesper Z., “Cathelicidin LL-37 Induces Angiogenesis via PGE2–EP3 Signaling in Endothelial Cells, In Vivo Inhibition by Aspirin,” Arterioscler. Thromb. Vasc. Biol., vol. 33, no. 8, pp. 1965–1972, Aug. 2013.
18. D. Xhindoli, S. Pacor, M. Benincasa, M. Scocchi, R. Gennaro, and A. Tossi, “The human cathelicidin LL-37 — A pore-forming antibacterial peptide and host-cell modulator,” Biochim. Biophys. Acta BBA – Biomembr., vol. 1858, no. 3, pp. 546–566, Mar. 2016.

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