LL-37 (CAP-18)

LL-37 and Inflammatory Diseases

LL-37, primarily recognized as an antimicrobial peptide, plays a role in various inflammatory diseases such as psoriasis, lupus, rheumatoid arthritis, and atherosclerosis. Depending on the local inflammatory environment and the specific cells involved, LL-37 exhibits various immune system-modulating behaviors, including:

• Reducing keratinocyte apoptosis.
• Increasing IFN-alpha production.
• Modifying the chemotaxis of neutrophils and eosinophils.
• Down-regulating signaling through toll-like receptor 4 (TLR4).
• Enhancing IL-18 production.
• Reducing levels of atherosclerotic plaques.

Interestingly, LL-37’s impact on the immune system varies depending on the context. In cell culture studies, it has been observed that LL-37 affects immune cells differently, with T-cells, for example, increasing their inflammatory actions in response to LL-37 when unactivated but decreasing inflammation when already activated. LL-37 seems to have significant homeostatic effects, helping to balance the immune response and prevent excessive inflammation in the presence of infection. This may explain the strong correlation between LL-37 levels and autoimmune diseases. Contrary to previous beliefs, recent evidence suggests that high LL-37 levels in autoimmune diseases may actually dampen inflammation rather than provoke it.

LL-37 Is a Potent Antimicrobial

LL-37 is a crucial component of the innate immune system and is rapidly activated in response to infections. Research in skin infections indicates that LL-37 levels in normal skin are low but increase rapidly when pathogens invade. LL-37 works in conjunction with other proteins, such as human beta-defensin 2, to combat infections.

LL-37 primarily acts by binding to bacterial lipopolysaccharide (LPS), a major component of the outer membrane of gram-negative bacteria. LPS is vital for the integrity of these bacteria’s membranes. LL-37’s ability to bind to and interfere with LPS makes it highly effective against certain bacteria, making it a potential treatment for serious bacterial infections. Additionally, LL-37 exhibits potent effects against gram-positive bacteria, which could make it useful in treating staph infections and other similar conditions.

LL-37 and Lung Disease

LPS, which contains LL-37’s target, is not exclusive to bacterial cell walls but is also found in various organisms and can become airborne in contaminated environments, leading to lung issues. Inhaling LPS triggers a response in lung tissue, which, unfortunately, often proves insufficient to prevent conditions like toxic dust syndrome, asthma, and COPD. Research is ongoing regarding the use of LL-37 as an inhaled treatment for toxic dust syndrome.

One intriguing discovery in LL-37 research related to lung disease is that the peptide promotes epithelial cell proliferation and wound closure in the airways. This indicates LL-37’s role as a crucial homeostatic regulator in the respiratory system, much like its role in immune function regulation.

Understanding LL-37 in Arthritis

Studies in rats have shown that LL-37 is found in high concentrations in joints affected by rheumatoid arthritis. However, it remains unclear whether the peptide is a causative factor or part of the body’s response to control the pathological process. Current evidence suggests that LL-37 is likely beneficial in inflammation rather than causative.

Research indicates that LL-37 deficiency does not affect the outcomes in animal models of arthritis or lupus, suggesting that LL-37 reactivity in arthritis is likely an incidental result of extensive over-expression in inflamed tissues. Mouse models of arthritis show that LL-37-derived peptides protect against collagen damage and reduce the severity of the disease. This protective activity may explain the high concentrations of LL-37 in tissues with substantial inflammation.

Arthritis has also been associated with an up-regulation of toll-like receptor 3, and LL-37’s effects on this receptor are still under investigation. LL-37’s selective reduction of pro-inflammatory responses in macrophages further supports its potential anti-inflammatory role.

LL-37 and the Intestine

LL-37 has several effects in the intestine, including increasing cell migration necessary for maintaining the intestinal epithelial barrier and reducing apoptosis during intestinal inflammation. Research suggests that LL-37 may be a useful adjuvant treatment in inflammatory bowel conditions, post-intestinal surgery, or during acute intestinal infections. Additionally, LL-37’s partnership with human beta defensin 2 aids in repairing and maintaining intestinal epithelium while reducing TNF-related cell death. The development of LL-37-based treatments could reduce reliance on TNF-alpha inhibitors in the treatment of inflammatory bowel disease.

LL-37 and Intestinal Cancer

Research indicates that LL-37 is beneficial in intestinal and gastric cancers, particularly those associated with smoking and tobacco use. The effects appear to be mediated through a vitamin D-dependent pathway, which may explain the reduced risk of GI cancer associated with vitamin D intake. LL-37 induces anti-cancer activity in tumor-associated macrophages via this pathway.

LL-37 and Blood Vessel Growth

LL-37 triggers the synthesis of prostaglandin E2 (PGE2) in endothelial cells, leading to angiogenesis (blood vessel growth). This ability to regulate angiogenesis has implications for cancer development, heart disease, stroke outcomes, wound healing, and more.