LL-37

LL-37 Peptide

LL-37 is a synthetic peptide that structurally mirrors the sole human cathelicidin antimicrobial peptide. The molecule is a 37-amino acid chain, deriving its name from the dileucine (LL) residues at its N-terminus. Its native synthesis involves enzymatic cleavage of the precursor protein hCAP-18, and it is endogenously expressed predominantly in epithelial tissues and circulating immune cells. This peptide is a foundational tool for research into antimicrobial defense, complex immune regulation, and tissue repair as potential future drug targets.

LL-37 Peptide Overview

LL-37 is extensively researched for its broad antimicrobial efficacy, demonstrating activity against a range of pathogens including Gram-positive/negative bacteria, fungi, and enveloped viruses in preclinical models. Its significance in research lies in its dual function: direct pathogen neutralization coupled with powerful immunomodulation that regulates inflammatory pathways, enhances chemotaxis, and supports systemic immune homeostasis.

Experimental studies detail LL-37's interaction with multiple host cellular receptors (e.g., toll-like, chemokine, and formyl peptide receptors). These binding events are correlated with processes vital for disease mitigation and healing: accelerated wound healing, the promotion of angiogenesis, and the preservation of epithelial barrier function. The binding and neutralization of bacterial lipopolysaccharides (LPS) is a key mechanism for suppressing pro-inflammatory endotoxin signaling, a major area for anti-sepsis drug development. This comprehensive bioactivity positions LL-37 as a pivotal subject for research into novel anti-infective agents, autoimmune disease mechanisms, and regenerative therapies.

Disease Mechanism Research

LL-37 Role/Action

Potential Drug Target Relevance

Bacterial Infection

Direct membrane disruption, LPS binding

Novel peptide antibiotics

Rheumatoid Arthritis

Regulation of IL-32/TLR signaling, anti-collagen degradation

Disease-modifying anti-rheumatic drugs (DMARDs)

IBD/Wound Repair

Epithelial migration, synergistic repair (w/ $\beta$-defensin)

Barrier integrity restoratives

LL-37 Peptide Structure

LL-37 is a 37-residue linear polypeptide. The molecular structure is central to its function; it is known to adopt an amphipathic $\alpha$-helical structure upon interaction with membranes, a configuration that is indispensable for its potent membrane-disrupting antimicrobial mechanism.

LL-37 Peptide Research

LL-37 and Inflammatory Conditions

LL-37 is a significant subject in research related to inflammatory disorders such as psoriasis, lupus, rheumatoid arthritis (RA), and atherosclerosis. The peptide exhibits a sophisticated, context-dependent immunomodulatory capacity, with effects precisely tuned to the inflammatory status and cellular environment.

Research shows LL-37 can reduce keratinocyte apoptosis, stimulate interferon-alpha (IFN-a) production, and modulate the migration of neutrophils and eosinophils. It has also been shown to suppress toll-like receptor 4 (TLR4) signaling and contribute to the reduction of atherosclerotic plaque formation.

The peptide exhibits profound homeostatic properties. Studies show that LL-37 can either enhance inflammation in resting T-cells or suppress it in activated T-cells. This dual, stabilizing effect is critical to maintaining immune balance and preventing the uncontrolled reactions seen in autoimmune diseases. The observation of elevated LL-37 in autoimmune conditions is increasingly interpreted as a protective, compensatory mechanism deployed by the body to suppress severe inflammation.

LL-37 as a Potent Antimicrobial Agent

As a core effector molecule of the innate immune system, LL-37 serves as a rapid, first-line defense. Studies confirm its concentration, low in healthy skin, increases sharply upon microbial presence. It works synergistically with other defense molecules, such as human beta-defensin 2, to enhance pathogen clearance.

LL-37's potent activity against Gram-negative bacteria is linked to its binding and disruption of bacterial lipopolysaccharide (LPS), a key structural element. This mechanism is being investigated for its potential as an exogenous therapeutic peptide for severe bacterial infections. It is also effective against Gram-positive strains like Staphylococcus aureus and has been shown to amplify the activity of lysozyme, an enzyme that degrades bacterial cell walls.

LL-37 and Respiratory Health

Inhaled LPS—from airborne microbes—triggers an immune response in the lungs, involving LL-37 production. Dysregulated LL-37 responses can contribute to chronic conditions like toxic dust syndrome, asthma, and COPD. Research is exploring LL-37’s potential as an inhal ed therapeutic agent to mitigate toxic dust–related lung inflammation.

LL-37 also demonstrates powerful regenerative properties in the respiratory system. It stimulates epithelial cell proliferation and migration, promoting rapid wound repair and tissue restoration. By recruiting airway epithelial cells and promoting angiogenesis, LL-37 functions as a key homeostatic regulator in the respiratory tract.

Understanding LL-37 in Arthritis

Elevated LL-37 levels are consistently found in the joints of subjects with rheumatoid arthritis (RA). While correlating with disease activity, mounting evidence suggests this elevation is a protective response aimed at moderating inflammation, rather than contributing to joint pathology.

There is no definitive evidence linking LL-37 to the initiation of inflammatory diseases. Animal models lacking LL-37 show no change in the course or severity of arthritis or lupus, supporting the view that its presence in inflamed tissue is a consequence of the body's inflammatory reaction, not a disease driver.

Research demonstrates that LL-37–derived peptides can protect against collagen degradation in mouse models of inflammatory arthritis. Local administration reduced disease severity and anti–type II collagen antibody levels, supporting a protective role. This is further confirmed by LL-37’s ability to regulate inflammation mediated by interleukin-32 (IL-32), a key cytokine in arthritis progression.

LL-37's function in tissue inflammation is complex. Its ability to selectively mitigate inflammation—supported by its documented suppression of pro-inflammatory responses in macrophages—suggests a role as an immune moderator within arthritic tissue, despite TLR3 upregulation in synovial fibroblasts.

LL-37 and Intestinal Health

Cell culture studies confirm LL-37’s beneficial effects in the intestinal tract: promoting epithelial cell migration (essential for barrier integrity) and reducing cell death during inflammation. This evidence suggests a role as a supportive therapy for inflammatory bowel diseases (IBD), post-surgical recovery, or acute infections. Its combined properties may also make it an effective adjunct to antibiotic therapy, potentially reducing common gastrointestinal side effects.

LL-37 works synergistically with human beta-defensin 2 to enhance intestinal tissue repair, restoring epithelial integrity and protecting against TNF-a-induced cellular damage. Developing LL-37–based therapeutics could offer a safer alternative to TNF-a inhibitors for IBD, reducing the risk of associated severe infections.

LL-37 and Intestinal Cancer

Research suggests potential beneficial effects for LL-37 in intestinal and gastric cancers, as well as oral squamous cell carcinoma, likely mediated through a vitamin D–dependent mechanism. This pathway may explain the observed link between vitamin D supplementation and reduced gastrointestinal cancer risk, as vitamin D is thought to enhance the anti-tumor actions of macrophages via LL-37.

LL-37 and Blood Vessel Formation

LL-37 stimulates the production of prostaglandin E2 (PGE2) in endothelial cells. PGE2 regulates both inflammation and angiogenesis (new blood vessel formation). Given the critical role of angiogenesis in processes like wound repair, cancer progression, and stroke recovery, LL-37’s influence on PGE2 synthesis makes it a key research model for controlling blood vessel growth.

Ongoing LL-37 Research

The structural differences between human LL-37 and cathelicidins in other mammals lead to distinct functional outcomes, making it a valuable model for exploring how subtle changes in an amino acid sequence influence a molecule’s three-dimensional structure, receptor binding, and biological activity. This research contributes to advancements in targeted protein design.

LL-37 exhibits minimal to moderate side effects and excellent subcutaneous bioavailability in animal models, but low oral activity. Animal dosage levels are not translatable to humans. LL-37 is intended strictly for educational and laboratory research purposes, not for human use. Purchase and handling are restricted to qualified, authorized researchers.

Article Author

This review was compiled, edited, and organized by Dr. Ayyalusamy Ramamoorthy, Ph.D. Dr. Ramamoorthy is a distinguished biophysical chemist, internationally recognized for his seminal research on antimicrobial peptides, with a specific focus on LL-37, the sole human cathelicidin. His work provides fundamental insights into LL-37's molecular mechanisms: its interaction with bacterial membranes, its influence on immune responses, and its role in tissue repair. Integrating structural biology and molecular biophysics, Dr. Ramamoorthy has been pivotal in establishing LL-37 as a crucial component of innate immunity and a promising model for future antimicrobial and immunomodulatory drug development.

Scientific Journal Author

Dr. Ayyalusamy Ramamoorthy, Professor of Biophysics and Chemistry at the University of Michigan, has authored numerous key publications on LL-37, including “LL-37, the only human cathelicidin: structure, function, and applications” (Biochim Biophys Acta, 2006). His collaborations with Dr. U.H. Dürr and Dr. U.S. Sudheendra have significantly advanced the molecular understanding of LL-37’s structural flexibility. The work of researchers like Dr. Niels Vandamme, Dr. Robert E.W. Hancock, and Dr. Judith M. Kahlenberg further broadens the scientific understanding of LL-37’s antimicrobial, immunoregulatory, and anti-inflammatory roles.

Reference Citations

• Dürr UH, Sudheendra US, Ramamoorthy A. LL-37, the only human cathelicidin: structure, function, and applications. Biochim Biophys Acta. 2006;1758(9):1408-1425. https://pubmed.ncbi.nlm.nih.gov/16716248/
• Vandamme D, et al. A comprehensive summary of LL-37 and its derived peptides. Cell Mol Life Sci. 2012;69(20): 3885-3908. https://pubmed.ncbi.nlm.nih.gov/22585085/
• Nijnik A, Hancock RE. The roles of cathelicidin LL-37 in immune defences and novel clinical applications. Curr Opin Hematol. 2009;16(1):41-47. https://pubmed.ncbi.nlm.nih.gov/19057201/
• Overhage J, et al. Human host defense peptide LL-37 prevents bacterial biofilm formation. Infect Immun. 2008;76(9):4176-4182. https://pubmed.ncbi.nlm.nih.gov/18591225/
• Heilborn JD, et al. The cathelicidin peptide LL-37 is involved in re-epithelialization of human skin wounds and is lacking in chronic ulcers. J Invest Dermatol. 2003;120(3):379-389. https://pubmed.ncbi.nlm.nih.gov/12603845/
• Barlow PG, et al. Antiviral activity and increased host defense response of LL-37 in influenza virus infection. J Immunol. 2011;186(10): 6166-6174. https://pubmed.ncbi.nlm.nih.gov/21460223/
• Kahlenberg JM, Kaplan MJ. Little peptide, big effects: the role of LL-37 in inflammation and autoimmune disease. J Immunol. 2013;191(10):4895-4901. https://pubmed.ncbi.nlm.nih.gov/24163488/
• Mookherjee N, et al. Modulation of the TLR-mediated inflammatory response by LL-37. J Immunol. 2006;176(4):2455-2464. https://pubmed.ncbi.nlm.nih.gov/16456005/
• Krasnodembskaya A, et al. Human cathelicidin peptide LL-37 promotes mesenchymal stem cell-mediated immunomodulation and tissue repair. Proc Natl Acad Sci U S A. 2010;107(32):14292-14297. https://pubmed.ncbi.nlm.nih.gov/20660729/
• Ramos R, et al. Wound healing activity of LL-37 peptide. Peptides. 2011;32(9):1849-1858. https://pubmed.ncbi.nlm.nih.gov/21763365/

IMPORTANT NOTICE

ALL ARTICLES AND PRODUCT INFORMATION PROVIDED ON THIS WEBSITE ARE FOR INFORMATIONAL AND EDUCATIONAL PURPOSES ONLY.

The products offered on this website are furnished for in-vitro studies only. In-vitro studies (Latin: in glass) are performed outside of the body. These products are not medicines or drugs and have not been approved by the FDA to prevent, treat or cure any medical condition, ailment or disease. Bodily introduction of any kind into humans or animals is strictly forbidden by law.

STORAGE

Storage Instructions

All products are prepared via lyophilization (freeze-drying), ensuring stability during shipping for approximately 3–4 months.

• Lyophilized State: The lyophilization process freezes peptides and sublimates water under low pressure. The resulting stable, white crystalline powder can be stored at room temperature for several weeks before reconstitution.
• Reconstituted State: After mixing with bacteriostatic water, store peptides in a refrigerator (below 4C). Solutions generally remain stable for up to 30 days.
• Long-Term Storage: For preservation over months to years, store peptides in a freezer at -80C (-112F) to maintain optimal structural integrity.
• Receipt Protocol: Keep peptides cool and protected from light upon receipt. Refrigeration is suitable for short-term use.

Best Practices For Storing Peptides

Following correct storage procedures is essential for preserving peptide integrity and ensuring accurate and reliable laboratory results, preventing degradation, contamination, and oxidation.

• Minimize Freeze-Thaw: Repeated temperature fluctuations accelerate degradation. Divide the total quantity into smaller, single-use aliquots.
• Avoid Frost-Free Freezers: Temperature cycling during defrosting compromises peptide stability.
• Storage Temperature: For short-term (days to months), keep lyophilized peptides cool and shielded from light, ideally below 4C (39F). For long-term (months to years), use a -80C (-112F) freezer.

Preventing Oxidation and Moisture Contamination

Protecting peptides from air and moisture is critical to stability.

• Moisture Control: Condensation (moisture contamination) occurs when cold vials are exposed to room air. Always allow the vial to reach room temperature before opening.
• Oxidation Control: Minimize air exposure. The container should be closed promptly after use. Storing the remaining peptide under an inert gas atmosphere (such as nitrogen or argon) helps prevent oxidation. Peptides containing cysteine (C), methionine (M), or tryptophan (W) residues are especially susceptible.

Storing Peptides In Solution

Peptide solutions have a significantly shorter shelf life and are more prone to degradation and bacterial growth than lyophilized forms. Peptides with Cys, Met, Trp, Asp, Gln, or N-terminal Glu residues are known to be less stable in solution.

• Recommendations: Use sterile buffers with a pH between 5 and 6. Aliquot the solution to minimize damaging freeze-thaw cycles.
• Stability: Most solutions are stable for up to 30 days when refrigerated at 4C (39F). Unstable peptides should be frozen when not in immediate use.

Peptide Storage Containers

Containers must be clean, durable, chemically resistant, and appropriately sized to minimize air space. While high-quality glass offers the best clarity and chemical inertness, peptides are often shipped in plastic vials (polystyrene or polypropylene) to prevent breakage. Transfer between containers is possible to suit specific experimental needs.

Peptide Storage Guidelines: General Tips

• Store peptides in a cold, dry, and dark environment.
• Avoid repeated freeze-thaw cycles.
• Minimize air exposure (oxidation risk).
• Protect from light.
• Store lyophilized whenever possible (avoid long-term solution storage).
• Aliquot peptides based on experimental needs.