LL-37

LL-37 Peptide

LL-37 is a synthetically produced peptide that structurally models the only human cathelicidin antimicrobial peptide. Defined by its 37-amino acid sequence, the peptide is named for its starting dileucine (LL) residues. In humans, LL-37 is generated by the enzymatic cleavage of the precursor protein hCAP-18 and is naturally concentrated in epithelial tissues and key immune cells. Laboratory research is intensively focused on LL-37's multifaceted actions in antimicrobial defense, immunomodulation, and tissue regeneration within in-vitro and preclinical study models.

LL-37 Peptide Overview

LL-37 is widely studied for its broad-spectrum antimicrobial efficacy, confirmed in preclinical models against a range of pathogens, including Gram-positive and Gram-negative bacteria, fungi, and enveloped viruses. Beyond its direct cytotoxic effects on microbes, LL-37 is a critical regulator of host defense mechanisms, influencing inflammatory cascades, promoting leukocyte chemotaxis, and establishing overall immune balance.

Research demonstrates that LL-37 engages with various host cellular receptors (e.g., toll-like, chemokine, and formyl peptide receptors). These binding interactions are correlated with beneficial processes like wound healing, the stimulation of angiogenesis (blood vessel growth), and the preservation of epithelial barrier function. A key mechanism involves LL-37 binding to bacterial lipopolysaccharides (LPS), which effectively neutralizes this endotoxin and suppresses the subsequent pro-inflammatory signaling. Its wide biological utility makes LL-37 a highly relevant subject for investigative studies into infection control, tissue engineering, and immune system therapeutic strategies.

LL-37 Mechanism

Biological Effect

Application Relevance (Research)

Membrane Disruption

Antimicrobial activity

Infection control, novel antibiotics

Receptor Interaction

Immune signaling, Chemotaxis

Autoimmune disease, Inflammation

Growth Factor Release

Epithelial migration, Angiogenesis

Wound healing, Tissue regeneration

LPS Binding

Endotoxin neutralization

Sepsis, inflammatory diseases

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LL-37 Peptide Structure

The LL-37 peptide is a linear sequence of 37 amino acids. Its functional versatility is intrinsically linked to its three-dimensional structure. It is known to adopt an amphipathic α-helical conformation when interacting with biological membranes, a structural feature crucial for its mechanism of action, particularly the disruption of bacterial cell membranes.

LL-37 Peptide Research

LL-37 and Inflammatory Conditions

Although known as an antimicrobial agent, LL-37 is deeply implicated in inflammatory disorders such as psoriasis, lupus, rheumatoid arthritis (RA), and atherosclerosis. The peptide’s effects are highly plastic, demonstrating a broad spectrum of immunomodulatory actions that depend on the specific inflammatory microenvironment and the cell types involved.

Key experimental findings show LL-37 can inhibit keratinocyte apoptosis, trigger the production of interferon-alpha (IFN-α), and regulate the migration of neutrophils and eosinophils. It also appears to suppress signaling through toll-like receptor 4 (TLR4), elevate interleukin-18 (IL-18) levels, and is linked to the reduction of atherosclerotic plaque formation. This highlights its significant role in both immune defense and the moderation of inflammatory processes.

The most notable discovery is the context-dependent nature of LL-37’s immune activity. In-vitro T-cell studies show that LL-37 can increase inflammatory output in resting cells but dampen it in already-activated cells. This dual, stabilizing mechanism suggests LL-37 possesses strong homeostatic properties, functioning to stabilize immune activity and potentially prevent the excessive, uncontrolled inflammation characteristic of autoimmune diseases. The observed upregulation of LL-37 in autoimmune conditions is increasingly viewed as a protective response aimed at suppressing severe inflammation and maintaining immune balance, rather than a driver of pathology.

LL-37 as a Potent Antimicrobial Agent

LL-37 is a core effector molecule of the innate immune system, mobilized rapidly as a first-line defense against infection. Studies on skin infection models demonstrate a swift increase in LL-37 levels in response to invading microbes, contrasting with the minimal levels in healthy tissue. The peptide is also known to exhibit synergistic activity with other antimicrobial molecules, such as human beta-defensin 2, enhancing infection control.

Its primary antimicrobial action is tied to its interaction with bacterial lipopolysaccharide (LPS), a critical component of Gram-negative outer membranes. By binding to and disrupting LPS, LL-37 compromises the structural integrity of the bacterial membrane. This mechanism is being explored for its therapeutic potential as an exogenous peptide in the management of severe bacterial infections. Though a primary target is Gram-negative species, LL-37 is also effective against Gram-positive bacteria, including Staphylococcus aureus. Furthermore, laboratory evidence indicates LL-37 can amplify the efficacy of lysozyme, an enzyme that breaks down bacterial cell walls, thus contributing to overall host defense.

LL-37 and Respiratory Health

Inhaled LPS—originating from various airborne microbes like bacteria or fungi—triggers an immune reaction in lung tissue, involving the production of LL-37. However, an insufficient or maladaptive response may contribute to chronic conditions such as toxic dust syndrome, asthma, and COPD. Researchers are currently investigating the utility of LL-37 as an inhaled therapeutic for mitigating toxic dust-related lung inflammation.

Recent findings also emphasize LL-37's regenerative potential within the respiratory system. The peptide stimulates the proliferation and migration of epithelial cells, accelerating wound repair and tissue restoration in the lungs. It facilitates the recruitment of airway epithelial cells to damaged sites and promotes angiogenesis to support new tissue growth. These roles suggest LL-37 is a key homeostatic regulator in the respiratory tract, complementing its established role in systemic immune balance.

Understanding LL-37 in Arthritis

Studies consistently report elevated LL-37 concentrations in the joints of subjects with rheumatoid arthritis (RA). While this increase is correlated with disease activity, the prevailing hypothesis is that this elevation signifies a protective, feedback mechanism aimed at moderating inflammation, rather than directly driving joint pathology.

Importantly, there is no definitive evidence to suggest LL-37 initiates or exacerbates inflammatory diseases. Animal models lacking the LL-37 peptide show no significant alteration in the severity or progression of arthritis or lupus. This suggests the peptide's abundance in inflamed tissue is a consequence of the body's reaction to inflammation, not a pathogenic cause. The immune reactivity observed against cathelicidins in arthritis is therefore considered an incidental effect of peptide overexpression at the site of inflammation.

Research in mouse models of arthritis demonstrates that LL-37–derived peptides can confer protection against the collagen degradation seen in inflammatory arthritis. Local administration of these peptides into affected joints has been shown to reduce disease severity and serum antibody levels against type II collagen, supporting a protective role. This hypothesis is further reinforced by LL-37's demonstrated ability to regulate inflammation mediated by interleukin-32 (IL-32), a key inflammatory cytokine in arthritis progression.

Arthritis pathology also involves the upregulation of toll-like receptor 3 (TLR3) in synovial fibroblasts. While LL-37's interaction with TLR4 exhibits both pro- and anti-inflammatory properties depending on the biological setting, ongoing research suggests LL-37 may function to selectively mitigate inflammation. Its documented ability to suppress pro-inflammatory responses in macrophages further supports its potential as an immune moderator within the arthritic joint environment.

LL-37 and Intestinal Health

In-vitro studies have revealed multiple beneficial effects of LL-37 on the intestinal tract. It promotes the migration of epithelial cells, which is essential for preserving intestinal barrier integrity, and reduces cell apoptosis during inflammatory episodes. This research suggests LL-37 could serve as a supportive agent for inflammatory bowel diseases (IBD), post-surgical recovery, or acute intestinal infections. Its combined antimicrobial and protective effects also propose a role as an adjunct to antibiotic therapy, potentially mitigating common gastrointestinal side effects.

Furthermore, LL-37 and human beta-defensin 2 work synergistically to enhance intestinal tissue repair. Laboratory data shows they cooperate to restore epithelial integrity while simultaneously protecting against cellular damage induced by TNF-α. The development of LL-37–based approaches could offer a safer therapeutic alternative to TNF-α inhibitors—the current standard for IBD—by potentially reducing the serious risk of secondary infections.

LL-37 and Intestinal Cancer

The link between LL-37 and cancer is complex, but evidence suggests potential beneficial effects in intestinal, gastric, and oral squamous cell carcinomas (the latter often linked to tobacco exposure). These protective effects appear to be mediated through a vitamin D–dependent pathway, potentially explaining the epidemiological link between vitamin D and reduced gastrointestinal cancer risk. Research suggests vitamin D enhances the anti-tumor function of macrophages via the LL-37 peptide.

LL-37 and Blood Vessel Formation

LL-37 has been shown to stimulate the production of prostaglandin E2 (PGE2) in endothelial cells. PGE2 is a pleiotropic molecule involved in both inflammation and angiogenesis (the formation of new blood vessels). While PGE2 contributes to inflammatory pain, its pro-angiogenic activity is central to critical biological processes, including wound repair, cancer progression, heart disease, and stroke recovery. LL-37’s ability to modulate PGE2 synthesis makes it an important subject for investigating the control of blood vessel growth in various therapeutic and pathological settings.

Ongoing LL-37 Research

A compelling area of study is the structural divergence between human LL-37 and cathelicidins in other mammals. Despite conserved core sequences, these molecular differences result in distinct functional profiles. LL-37 is thus an invaluable model for illustrating how subtle changes in amino acid sequence can dramatically influence a molecule’s tertiary structure, receptor-binding affinity, and biological outcome. This research contributes significantly to the field of biochemistry by advancing methods for targeted protein design and manipulation.

LL-37 is noted for producing minimal to moderate side effects and demonstrating excellent subcutaneous bioavailability in animal models, though oral activity is poor. Crucially, animal dosage levels cannot be extrapolated for human use. This LL-37 product is intended solely for educational and laboratory research purposes and is not authorized for human use. Only qualified, authorized researchers should purchase and handle this product.

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 pioneering research on antimicrobial peptides, with a specific focus on LL-37, the sole human cathelicidin. His work has provided fundamental insights into LL-37's molecular mechanisms: how it interacts with bacterial membranes, modulates immune responses, and facilitates tissue repair. By integrating structural biology and molecular biophysics, Dr. Ramamoorthy has been pivotal in defining LL-37 as a vital 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, is the author or co-author of numerous seminal papers on LL-37, including “LL-37, the only human cathelicidin: structure, function, and applications” (Biochim Biophys Acta, 2006). His collaborative work with Dr. U.H. Dürr and Dr. U.S. Sudheendra has significantly enriched the molecular understanding of LL-37’s structural flexibility and functional diversity. The contributions of other researchers, such as Dr. Niels Vandamme, Dr. Robert E.W. Hancock, and Dr. Judith M. Kahlenberg, collectively form a robust scientific foundation for the ongoing biomedical investigation of LL-37's antimicrobial, immunoregulatory, and anti-inflammatory properties.

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), which provides structural stability for approximately 3–4 months during shipping.

• Lyophilized State: Lyophilization is a specialized process involving the freezing of peptides and sublimation of water under low pressure. The resulting stable, white crystalline powder can be stored at room temperature for several weeks until reconstitution.
• Reconstituted State: Peptides must be stored under refrigeration (below 4C) after reconstitution with bacteriostatic water. Solutions typically maintain stability for up to 30 days.
• Extended Storage: For long-term preservation (months to years), peptides should be stored in a freezer at -80C (-112F). This temperature is ideal for maintaining the peptide’s structural integrity.
• Handling on Receipt: Peptides must be kept cool and shielded from light. For short-term use (days, weeks, or a few months), refrigeration is sufficient.

Best Practices For Storing Peptides

Strict adherence to storage protocols is essential for maintaining the accuracy and reliability of experimental results. Proper storage minimizes degradation, contamination, and oxidation, preserving peptide integrity over time.

• Avoid Freeze-Thaw Cycles: Repeated temperature fluctuations accelerate degradation. It is best practice to aliquot the total quantity into smaller, single-use portions.
• Frost-Free Freezers: Avoid storing peptides in frost-free freezers, as the temperature cycles during defrosting can compromise stability.
• Environment: Store lyophilized peptides in a cold, dry, and dark environment.

Preventing Oxidation and Moisture Contamination

The stability of peptides is significantly compromised by exposure to air and moisture.

• Moisture Control: Condensation (moisture contamination) is a risk when a cold vial is opened. Always allow the frozen or refrigerated peptide vial to reach room temperature before opening.
• Oxidation Control: The container should be closed promptly after use. Storing the remaining peptide under an inert gas atmosphere (such as nitrogen or argon) can prevent oxidation. Peptides containing oxidizable residues like cysteine (C), methionine (M), or tryptophan (W) require particular care.

Storing Peptides In Solution

Peptide solutions have a notably shorter shelf life and are prone to bacterial degradation. Peptides with Cys, Met, Trp, Asp, Gln, or N-terminal Glu residues are known to degrade more rapidly in liquid form.

• Protocol: If solution storage is necessary, use sterile buffers with a pH range of 5 to 6. Aliquot the solution to minimize 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 to maintain structural integrity.

Peptide Storage Containers

Containers must be clean, durable, chemically resistant, and sized appropriately to minimize unnecessary air space. Both glass and plastic (polystyrene or polypropylene) vials are used. High-quality glass offers optimal clarity and chemical inertness. Peptides are frequently shipped in plastic to prevent breakage; transfer to glass or plastic is acceptable based on experimental needs.

Peptide Storage Guidelines: General Tips

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