LL-37 (5mg)

What is the LL-37 Peptide?

LL-37 is the only known human Cathelicidin, a big protein family where the members exhibit diverse functions. These peptides, which are produced by macrophages and polymorphonuclear leukocytes (both types of white blood cells), have bactericidal action. They have been found to have shown other substantial effects as well. The entire group is often referred to as antimicrobial peptides (AMPs). LL-37, in particular, has been researched in relation to autoimmune disease, cancer, and wound healing.^[1] For example, researchers note that “Corneal and conjunctival epithelia express LL-37 as part of mucosal innate immunity to protect against bacterial and viral ocular infections.”

LL-37 Peptide Research

Specifications

AKA: CAP-18

Molecular Formula: C205H340N60O53

Molecular Weight: 4493.33 g/mol

Sequence: Leu-Leu-Gly-Asp-Phe-Phe-Arg-Lys-Ser-Lys-GluLys-Ile-Gly-Lys-Glu-Phe-Lys-Arg-Ile-Val-Gln-Arg-Ile-Lys-Asp-Phe-Leu-Arg-Asn-Leu-Val-Pro-ArgThr-Glu-Ser

PubChem: CID 16132341

CAS Number: 154947-66-7

Reconstitution: Required

LL-37 and Inflammatory Diseases
LL-37, although essentially known to be an antimicrobial peptide, is also involved in different inflammatory diseases such as lupus, rheumatoid arthritis, psoriasis, and atherosclerosis. LL-37 researchers suggest the peptide’s diverse immune system modulating behaviors based on the type of cells involved and the local inflammatory environment. It has been suggested to:
– reduce apoptotic death of keratinocytes
– improve IFN-alpha synthesis
– suppress signaling through toll-like receptor 4 (TLR4)
– modify chemotaxis of neutrophils and eosinophils^[2]
– trigger IL-18 production
– reduce levels of atherosclerotic plaques
Interestingly, LL-37 (aka CAP-18) appears to stimulate the immune system in a different manner depending on the trigger. Cell culture studies have observed the importance of the inflammatory environment in determining the immune response to LL-37. T-cells appear to improve their inflammatory actions because of LL-37 when they are not activated, but minimize the inflammatory action when already activated. The peptide appears to mediate homeostasis of immunological response, thus controlling it from being hyperactive when the body suffers from an infection. It may help to control levels of inflammation in autoimmune diseases. There is a strong correlation between the peptide levels and the extent of the disease. Initially, LL-37 / CAP-18 was thought to promote autoimmune disorders, but recent results have suggested it may actually help to abate the damage.^[3] The researchers outline that the peptide has a role in “in the modulation of immune and inflammatory pathways and their effects on autoimmune and inflammatory diseases.” High levels of the peptide may thus help check further increased inflammation.

LL-37 and Antimicrobial Properties
LL-37 appears to be an important biomolecule of innate immunity and one of the initial proteins to activate when faced with an infection. Research in skin infections observes that the peptide, though present in very few amounts in the skin, appears to accumulate very fast when invading pathogens are present.^[4] It may work in conjunction with other proteins, like human beta-defensin 2, to fight infection. LL-37 appears to bind to bacterial lipopolysaccharide (LPS) of the outer membrane of gram-negative bacteria. LPS is critical for the membrane integrity of these bacteria. The possible ability of LL-37 to bind to and interfere with LPS makes it toxic for certain bacteria. Thus, it may be used exogenously to treat serious bacterial infections in people. LL-37 may be powerful against gram-positive pathogens, treating staph infections and other serious bacteria. In vitro research indicates that LL-37 / CAP-18 may improve lysozyme’s effects, which destroys gram-positive bacteria like Staph aureus.

LL-37 and Lung Disease
LPS is found in several different organisms and, in some instances, becomes airborne when an environment is contaminated by mold or other fungi. Normal lung tissue responds by producing mucus upon LPS inhalation. Unfortunately, the response is often insufficient to intercept toxic dust syndrome and respiratory diseases like asthma and COPD, to name a few. LL-37 is being considered as an inhaled treatment for toxic dust syndrome.^[5] LL-37 appears to promote the proliferation of epithelial cells and the closure of wounds in lung diseases. The peptide may attract airway epithelial cells to injury sites and help vascularization, wound healing, and supply of nutrition to the newly formed tissue. Thus the peptide is a potential mediator for homeostasis in airways like in immune function.

LL-37 Peptide and Arthritis
Research in rats models observed high LL-37 levels in joints of rats suffering from rheumatoid arthritis. Interestingly, it is yet unknown if is the cause or cure for the condition. However, several findings indicate the therapeutic potential of the peptide in inflammation. LL-37 deficiency does not change the outcomes in animal models of arthritis or lupus.^[6] Animals expressing the peptide may show the same disease outcome as those lacking the peptide. These results indicate that the physiological reactions in enhanced levels of cathelicidins in arthritis are incidental.
Peptides derived from LL-37 may reduce collagen damage which occurs in inflammatory arthritis. Direct introduction of these peptides to arthritic joints in rats was observed to reduce both the severity of the disease as well as serum levels of antibodies against type II collagen. Direct involvement of interleukin-32 (IL-32) in the severity of inflammatory arthritis has been reported. LL-37 and its derivatives may have the ability to regulate the level of IL-32 response. Hence, it would be reasonable speculation that the peptide is protective in this disease scenario.
Synovial fluid fibroblasts increase toll-like receptor 3 levels, which worsens the arthritic condition by increasing inflammatory cytokine expression. LL-37 may interact with TLR4 and either promote pro-inflammatory or anti-inflammatory outcomes.^[7] It is yet to be confirmed if LL-37 / CAP-18 mediates the same effect against the backdrop of increased TLR3. The peptide has been reported in experimental studies to selectively decrease pro-inflammatory macrophage responses, thus suggesting its regulation of inflammation to be selective.

LL-37 and Intestinal Cancer
Cell culture-based research studies have suggested multiple functions of LL-37 in the intestine. The peptide appears to improve the migration of cells necessary for epithelial barrier maintenance of the intestine. LL-37 also may reduce apoptosis when there is intestinal inflammation, helping to decline the causes of inflammation and the associated pathogenesis. The peptide may behave as a useful adjuvant for the treatment of inflammatory bowel conditions post intestinal surgery, during acute intestinal infections a well as for oral antibiotic therapy thus potentially preventing GI side effects. Studies suggest LL-37 pairs with human beta-defensin 2 to help in wound healing. In vitro work indicates that the peptides work simultaneously to repair and maintain the intestinal epithelium while decreasing TNF-related cell death.^[8] Despite being the principal medicines used for the treatment of inflammatory bowel conditions, TNF-alpha inhibitors have various adverse side effects. They increase the chances of tuberculosis infection to a great extent. LL-37 based treatment will potentially reduce the dependence on TNF-alpha inhibitors and, thereby mortality rate. Research in use of the peptide for cancer treatment has generated mixed reports. However, it was generally observed to be effective in intestinal, gastric, and oral carcinomas associated with smoking and tobacco use. The treatment appears to be vitamin D dependent, as vitamin D promotes the anti-cancer function of tumor-associated macrophages through LL-37 / CAP-18.

LL-37 and Blood Vessel Growth
The peptide appears to help produce prostaglandin E2 (PGE2) in endothelial cells. In endothelial cells, PGE2 promotes the development of blood vessels via a process called angiogenesis. It is crucial to regulate angiogenesis as it impacts cancer development, stroke outcomes, heart disease, wound healing, and more. LL-37 helps to study angiogenesis in-depth to promote it in cardiac disease and discourage cancer milieu.

Ongoing LL-37 / CAP-18 Peptide Research

The peptide varies in the structure of its human isoform compared to other animals. This increases its functional versatility by allowing interaction with different receptors. This feature helps scientists to study the impact of amino acid modulation to achieve specific functional outcomes. LL-37 research reports minimal to moderate side effects, low oral bioavailability and excellent subcutaneous bioavailability in murine models. The dosage (per kg) in mice does not match up to humans.

References