LL-37

What Is LL-37 ?

LL-37, like all cathelicidins, has antimicrobial, antibacterial, antiviral, and anti-fungal effects, and it has been shown to reduce inflammation. Research also shows that it works against certain cancers and encourages blood vessel growth in specific settings.

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
Molecular Weight: 4493.342 g/mol
PubChem CID: 16198951
CAS Number: 154947-66-7
Synonyms: CAP-18, Cathelicidin, antibacterial peptide LL-37

Inflammatory Diseases
LL-37, while mainly known as an antimicrobial peptide, plays a role in several inflammatory diseases like psoriasis, lupus, rheumatoid arthritis, and atherosclerosis. Depending on the local inflammatory setting and the cells involved, LL-37 has various ways of adjusting the immune system. It has been found to:
– reduce keratinocyte cell death,
– increase IFN-alpha production,
– change how neutrophils and eosinophils move toward infection sites,
– lower signaling through toll-like receptor 4 (TLR4),
– boost IL-18 production, and
– decrease levels of atherosclerotic plaques.
Interestingly, LL-37 does not affect the immune system the same way every time. Cell culture studies show that the inflammatory environment influences how immune system cells respond to LL-37. For example, T-cells increase their inflammatory actions in response to LL-37 when not activated but decrease them when already activated. It seems LL-37 has strong balancing effects, helping to steady the immune response and prevent it from overreacting during infection. These findings suggest LL-37 could help regulate the uncontrolled inflammation in autoimmune diseases. This may explain the strong link between LL-37 levels and autoimmune disease. It was once thought LL-37 might cause autoimmune inflammation, but newer evidence suggests high levels in autoimmune disease may actually prevent more severe inflammation.
Antimicrobial Effects
LL-37 is part of the innate immune system and one of the first parts activated during infection. Studies in skin infections suggest normal skin has very low LL-37 levels, but the peptide builds up quickly when pathogens invade. The peptide works together with other proteins, like human beta-defensin 2, to fight infection.
LL-37 mainly works by binding to bacterial lipopolysaccharide (LPS), a key part of the outer membrane in gram-negative bacteria. LPS is vital for membrane strength in these bacteria. LL-37’s ability to bind and disrupt LPS makes it very deadly to certain bacteria. This could make it useful for treating serious bacterial infections in people.
Even though LL-37 focuses on gram-negative bacteria’s cell membrane parts, it still has strong effects against gram-positive bacteria too. This could make it helpful for staph infections and other serious bacteria. Lab studies show LL-37 boosts the effects of lysozyme, an enzyme that destroys gram-positive bacteria like Staph aureus.
Lung Disease
LPS, as mentioned, is not just in bacterial cell walls. It appears in various organisms and sometimes becomes airborne in moldy or fungi-contaminated areas. When inhaled, normal lung tissue responds by making LL-37. Unfortunately, the response is often not enough to prevent toxic dust syndrome and the start of respiratory diseases like asthma, COPD, and others. Research into using LL-37 as an inhaled treatment for toxic dust syndrome is ongoing.
One interesting finding from studies on LL-37’s effects in lung disease is that the peptide promotes the growth of epithelial cells and wound closure. It seems one of LL-37’s main roles in the lungs is to draw airway epithelial cells to injury sites and promote both wound healing and the growth of blood vessels needed for nutrients in new tissue. It appears LL-37 is a key regulator of balance in the airways, just as it balances immune function.
Arthritis
Studies in rats show LL-37 is found in high amounts in joints affected by rheumatoid arthritis. In particular, the peptide seems linked to arthritis’s harmful events. It is not clear, though, if the peptide causes it or if its increase in these joints is the body’s attempt to control the harmful process. Several things suggest LL-37 is helpful in inflammation and not causing it.
First, there is no evidence that LL-37 or any other cathelicidin causes inflammatory disease. This does not fully rule out the peptide as a cause, but the evidence leans against it. In particular, lacking LL-37 does not change outcomes in animal models of arthritis or lupus. In other words, animals without LL-37 have the same disease progression as those with the peptide. Based on these findings, scientists suggest that reactions against cathelicidins in arthritis are likely a side effect from high peptide levels in inflamed tissues. In other words, it is not the main issue.
Studies in mouse models of arthritis show peptides from LL-37 protect against collagen damage common in inflammatory arthritis. Giving these peptides directly to affected joints reduces disease severity and blood levels of antibodies against type II collagens. Based on this study, it is reasonable to think LL-37 likely protects in arthritis, which could explain its high levels in inflamed tissues. This idea is supported by LL-37 and its versions regulating inflammation from interleukin-32, a molecule directly linked to inflammatory arthritis severity.
Arthritis has also been linked to an increase in toll-like receptor 3 in synovial fluid fibroblasts, a factor that worsens arthritis by raising inflammatory cytokine levels. LL-37 has been shown to bind to TLR4 and either boost pro-inflammatory or anti-inflammatory effects. Which it does when TLR3 is increased is not clear, but research continues. The idea that it might selectively reduce inflammation is reasonable, given LL-37 has been found to selectively lower pro-inflammatory macrophage responses before.
Intestinal Health
Cell culture studies show LL-37 has several effects in the intestine. First, the peptide boosts movement of cells needed to maintain the gut’s epithelial barrier. Second, LL-37 reduces cell death during gut inflammation, helping slow various inflammatory conditions. Overall, the research suggests LL-37 may be a useful add-on treatment for inflammatory bowel conditions, after gut surgery, or during acute gut infections. It may even help as an add-on to antibiotic therapy, preventing the gut side effects that often limit oral antibiotics.
LL-37 does not work alone in the gut, teaming up again with human beta defensin 2 to promote wound healing. Cell culture studies show the peptides work together to repair and maintain gut lining while reducing TNF-related cell death. Currently, TNF-alpha blockers are a main treatment for inflammatory bowel conditions. They work well but have serious side effects, including a big rise in risk of severe infections like tuberculosis. Developing LL-37-based treatments for inflammatory bowel disease could reduce reliance on TNF-alpha blockers and improve health outcomes in this group.
Intestinal Cancer
Studies on LL-37 and cancer have mixed results, but the peptide seems helpful for gut and stomach cancers, including oral squamous cell carcinoma linked to smoking and tobacco. Interestingly, these effects seem to work through a vitamin D-dependent pathway, which may explain why taking vitamin D has been linked to lower gut cancer risk. It appears vitamin D triggers the anti-cancer activity of tumor-related macrophages via LL-37.
Blood Vessel Growth
LL-37 seems to trigger prostaglandin E2 (PGE2) synthesis in endothelial cells. PGE2 links to both inflammatory pain and blood vessel growth, but these effects vary by location. In endothelial cells, PGE2 triggers blood vessel development in a process called angiogenesis. This can be good or bad, depending on the situation. Regulating angiogenesis has been a focus of much research in recent decades because it affects cancer growth, heart disease, stroke outcomes, wound healing, and more. LL-37’s activity provides a useful way to study the angiogenesis pathway and a model for future treatments to both promote blood vessel growth when needed (like in heart disease) and discourage it when harmful (like in cancer).