LL-37 (5mg)

Description

What is LL-37?

LL-37, also called Cathelicidin, is a cationic peptide composed of 37 amino acids, and is primarily found in the neutrophils in the human body (1).

LL-37 is produced by the extracellular breakdown of the hCAP18 proteins caused by protease enzymes. Known for its antimicrobial properties, LL-37 forms agglomerates and lipid bilayers, due to which it is not easily degraded in the body and is protected from enzymatic action (1).

Peptides such as LL-37 help in defending and protecting one’s immune system against several infections.

Maintaining the body’s innate immune system is vital for a healthy well-being. Immunity helps fight against several disorders, injuries, and any disturbances to the natural bodily functions, and thereby helps protect the human system.

There are many immunodeficiency disorders that can either be inherent by birth or acquired as a consequence of another ailment, and autoimmune diseases. During such diseased conditions, the body’s immune system diminishes and fails to protect the body. Aging is also another factor which causes gradual weakening of the immune system.

LL-37 Discovery

Antimicrobial peptides were first discovered in 1980 by the Boman group (2).

Over the last 40 years, these peptides have been vigorously researched and studied, and by 2010, an antimicrobial peptide database was created by Wang and Wang, which has over 1500 references (2).

How does LL-37 Function?

Antimicrobial peptides are structured to fight against bacteria, fungi, and various viruses. These peptides interact with these targets in a non-specific fashion which explains why the pathogens are unable to develop resistance against these peptides (2).

LL-37 is a vital α-helical peptide that is required to maintain human immunity against all microbes (3).

To understand the functioning of the peptide, a peptide model was created as part of a study (4) based on the assumption that the peptide interacts directly with the bacterial membrane. This study determined that the peptide first interacts with the lipids on the bacterial membrane via electrostatic characteristics, followed by lateral diffusion and consequent assembly of the peptide on the membrane. This is how the peptide binds and thereby diffuses the bacterial membrane leading to its destruction.

There are several other studies that describe how the peptide interacts with microbial membranes including pore formation on the membrane by the peptide (3,5) and extreme membrane disruption caused by the peptide and lipid complexes (6).

All the studies conclude that LL-37 peptides interact with the microbial membrane leading the membrane breakdown and ultimate microbial cell death.

What are the Uses of Cathelicidin Peptide?

The various uses and benefits of LL-37 peptide include the following:

• Antimicrobial effects against bacteria, virus, fungi
• Inflammation
• Angiogenesis
• Wound healing and tissue repair
• Controls infection
• Potential use in treating SARS-CoV-2 infection (COVID-19 treatment)
• Potential use in treating cancer and as immunotherapeutics

Research and Clinical Studies

Inflammatory Response

The main aim of this study (7) was to determine the inflammatory effects of the LL-37 peptide in the human body.

Human tissue culture was used for this in vitro study, half of which was used as is and to the other half, the U1 RNA was added. U1 RNA is a non-coding RNA found in abundance in the human body and is released upon tissue injury. LL-37 peptide was then added to both cultures.

Upon genetic analysis, it was seen that the culture that was treated with both U1 RNA and LL-37 peptide had a significant response towards epidermal (skin) inflammation and defense response.
This study demonstrated that upon injury, LL-37 triggers a systemic response which leads to inflammation and defense mechanisms in the human body.

Role of LL-37 in Inflammatory Disorders

Psoriasis and LL-37 Studies

The main aim of this study (1) was to understand the role of LL-37 in the prognosis of Psoriasis condition. Psoriasis is a skin diseased condition characterized by increased inflammation, redness, and itchy skin. Levels of LL-37 increase in this diseased condition.

Disease pathogenesis study has shown that endogenous LL-37 peptide forms complex with DNA which leads to a series of reactions in the body leading to increased interferon mechanism and more inflammatory responses.

This study demonstrated that while increased LL-37 is favorable for tissue and wound injury, it should be noted that elevated LL-37 levels may be indicative of psoriasis condition. Studies on whether LL-37 can be used as a diagnostic tool for psoriasis condition are yet to be determined.

Arthritis and LL-37 Studies

Elevated levels of LL-37 are common in patients suffering from rheumatoid arthritis. The main objective of this study (1,8) was to evaluate the role of LL-37 in this disease condition.

A group of rats were used in this study (8) where one was the control group and the other was experimentally induced with rheumatoid arthritis. Upon inducing the condition, there was an increased regulation of rCRAMP, which is the rat analog of human LL-37 peptide, in inflammatory cells. LL-37 then further induced apoptosis of osteoblasts (cells that form new bones), thereby leading to decreased bone formation in the joints.

This study demonstrated that increased LL-37 levels are characteristic to joint ache and arthritis and may potentially be used for diagnostic purposes.

Besides these, study(1) has shown the LL-37 elevation is also seen in other inflammatory diseases such as arteriosclerosis. LL-37 activation and the consequent upregulation of interferons are characteristic to arteriosclerosis induced cells. This suggests that LL-37 plays a vital role in various autoimmune inflammatory diseases and can be potentially used as the diagnostic tool and as immunomodulatory agents for these conditions.

Wound Healing Effects

In this study(9), dexamethasone treated mice were administered with LL-37 to study the effects of this peptide on angiogenesis and wound healing. Dexamethasone is a medication to treat inflammatory conditions in humans. LL-37 peptide was applied topically to these mice.

It was seen that the peptide treated mice showed increased results of vascularization and formation of skin cells which further escalates the process of skin healing and wound repair.

This study demonstrated that LL-37 induces endothelial skin cell proliferation and formation of tubule-like structures, which are both required in wound healing (angiogenesis) mechanisms.

Anti-cancer Effects of LL-37

Studies (10) are ongoing to establish the use of LL-37 peptide in treating cancer development including ovarian and breast cancer. Studies (10) have shown that LL-37 inhibits gastric cancer cell proliferation by way of activation of bone morphogenetic protein signaling system.

The main aim of this research (10) was to establish the use of LL-37 as an immunotherapeutic agent, or atleast establish the use of LL-37 peptide as an adjuvant in eliminating cancer cells from the host system.

CpG oligodeoxynucleotides are widely used immunotherapeutic agents as it promotes the tumor suppressing activities in the body. When administered with LL-37, the peptide LL-37 increases the CpG oligodeoxynucleotides sensitivity in lymphocytes and natural killer cells which elevate the anti-tumor activity of the peptide.

Furthermore, CpG oligodeoxynucleotides and LL-37 coadministration increases the proliferation and activation of natural killer cells, that in turn further stimulates the anti-tumor activity of the peptides.

Effects of LL-37 on GI Tract

LL-37 plays a significant role in many ailments associated with the gastrointestinal (GI) tract. There is an increased expression of LL-37 in the patients suffering from stomach ulcers and Crohn’s disease. Owing to its antimicrobial effect, LL-37 has the ability to protect stomach and GI mucosa from any microbial damage.

Interestingly, low levels of LL-37 in patients suffering from irritable bowel disease have shown slow progress in treating the GI tract mucosa, which further emphasizes that LL-37 has positive effects on GI disorders (12).

COVID-19 Research

COVID-19 is an ongoing pandemic that consumed millions of lives due to the SARS-CoV-2 infection caused in human lungs. There are several studies being conducted on various medications to determine how to control and potentially treat COVID-19.

The main purpose of this study (11) was to evaluate the effects of LL-37. A SARS-CoV-2 pseudovirion was employed as part of the study and administered to the human kidney cell structure along with an increasing dose of synthetic LL-37. Study results showed that LL-37 blocked the pseudovirion infection (analogous to SARS-CoV-2 infection) at a dose of approximately 4.75 microg/mL.

The possible mechanism through which LL-37 acts is via binding (or cloaking) to the angiotensin converting enzyme (ACE), as a result of which SARS-Cov-2 is unable to bind with these enzymes and hence unable to spread the infection.

Further study was conducted on the mice model that was treated with SARS-CoV-2 pseudovirion to experimentally induce the Covid infection. Once induced, LL-37 was administered in the mice via the intranasal route of administration. The outcome of the study was that LL-37 peptide was able to significantly reduce the SARS-CoV-2 infection.

While the studies show promising effects of LL-37 in COVID-19 treatment, it should be noted that all experiments were conducted with SARS-CoV-2 pseudovirion and not the actual virus. Hence, these results do not accurately depict the activity of LL-37 in SARS-Cov-2 infection in vivo. Research is still ongoing to experimentally establish the safe, therapeutic use of LL-37 peptide in treating COVID-19 disorder.

Side Effects of LL-37 Peptide

The common side effects of LL-37 are similar to the other peptide administration, including:

• Pain and itchiness at the site of administration
• Lethargy, fatigue
• Flushes, headache
• Nausea
• Overproduction / overdose may lead to the onset of autoimmune diseases (1)

While LL-37 peptide possesses immunoprotective effects, overproduction (or overdose of the peptide) may lead to autoimmune disorders such as rheumatoid arthritis, psoriasis, and systemic lupus erythematosus (SLE). There is no reported case of such side effects so far, however, studies have shown this as a probable adverse effect of the peptide causing dysregulation in the body’s immune system.

Summary

LL-37 is a potent cationic peptide composed of 37 amino acids, which is produced naturally in the body and is also available in the synthetic form.

While the working mechanism of LL-37 is still unclear, there are various theories to support that the peptide exerts its effects by acting on the microbial membrane. The peptide binds with the lipids found on the membranes and causes membrane disruption, which ultimately leads to microbial cell death.

There are various health benefits of LL-37 peptide besides its immuno protecting abilities, including immunomodulatory properties, ability to induce inflammation and defense mechanisms in the body, and wound healing properties. LL-37 has a wide spectrum of activity as it is able to act against bacteria, fungi, and viruses.

LL-37 has shown promising results against COVID-19 and has the potential to be used as a therapeutic agent in the treatment of SARS-CoV-2 infection. However, further experiments and clinical trials are yet to be conducted to evaluate the full potential and scope of the peptide use in treating the pandemic virus.

References:

1. Kahlenberg, J Michelle, and Mariana J Kaplan. “Little peptide, big effects: the role of LL-37 in inflammation and autoimmune disease.” Journal of immunology (Baltimore, Md. : 1950) vol. 191,10 (2013): 4895-901. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836506/

2. Seil, M., Nagant, C., Dehaye, J. P., Vandenbranden, M., & Lensink, M. F. (2010). Spotlight on Human LL-37, an Immunomodulatory Peptide with Promising Cell-Penetrating Properties. Pharmaceuticals, 3(11), 3435–3460. h https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4034075/

3. Zeth, Kornelius, and Enea Sancho-Vaello. “The Human Antimicrobial Peptides Dermcidin and LL-37 Show Novel Distinct Pathways in Membrane Interactions.” Frontiers in chemistry vol. 5 86. 7 Nov. 2017. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5681987/

4. Brogden KA. Antimicrobial peptides: pore formers or metabolic inhibitors in bacteria? Nat Rev Microbiol. 2005 Mar;3(3):238-50. https://pubmed.ncbi.nlm.nih.gov/15703760/

5. Ludtke SJ, He K, Heller WT, Harroun TA, Yang L, Huang HW. Membrane pores induced by magainin. Biochemistry. 1996 Oct 29;35(43):13723-8. https://pubmed.ncbi.nlm.nih.gov/8901513/

6. Bechinger B, Lohner K. Detergent-like actions of linear amphipathic cationic antimicrobial peptides. Biochim Biophys Acta. 2006 Sep;1758(9):1529-39. https://pubmed.ncbi.nlm.nih.gov/16928357/

7. Takahashi, T., Kulkarni, N.N., Lee, E.Y. et al. Cathelicidin promotes inflammation by enabling binding of self-RNA to cell surface scavenger receptors. Sci Rep 8, 4032 (2018). https://doi.org/10.1038/s41598-018-22409-3

8. Hoffmann MH, Bruns H, Bäckdahl L, Neregård P, Niederreiter B, Herrmann M, Catrina AI, Agerberth B, Holmdahl R. The cathelicidins LL-37 and rCRAMP are associated with pathogenic events of arthritis in humans and rats. Ann Rheum Dis. 2013 Jul;72(7): https://pubmed.ncbi.nlm.nih.gov/23172753/

9. Ramos R, Silva JP, Rodrigues AC, Costa R, Guardão L, Schmitt F, Soares R, Vilanova M, Domingues L, Gama M. Wound healing activity of the human antimicrobial peptide LL37. Peptides. 2011 Jul;32(7):1469-76. doi: 10.1016/j.peptides.2011.06.005. Epub 2011 Jun 13. https://pubmed.ncbi.nlm.nih.gov/21693141/

10. Wu, W. K., Wang, G., Coffelt, S. B., Betancourt, A. M., Lee, C. W., Fan, D., Wu, K., Yu, J., Sung, J. J., & Cho, C. H. (2010). Emerging roles of the host defense peptide LL-37 in human cancer and its potential therapeutic applications. International journal of cancer, 127(8), 1741–1747. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2930073/

11. Wang, C., Wang, S., Li, D., Chen, P., Han, S., Zhao, G., Chen, Y., Zhao, J., Xiong, J., Qiu, J., Wei, D. Q., Zhao, J., & Wang, J. (2021). Human Cathelicidin Inhibits SARS-CoV-2 Infection: Killing Two Birds with One Stone. ACS infectious diseases, 7(6), 1545–1554. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056948/

12. Kusaka; et al. Expression of human cathelicidin peptide LL-37 in inflammatory bowel disease. Clin Exp Immunol. 2018 Jan;19(11). Epub 2017 Sep 28. https://pubmed.ncbi.nlm.nih.gov/28872665/

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Synonyms/Aliases: LL-37, Cathelicidin

NOTE: These products are intended for laboratory research use only. LL-37 for sale is not intended for personal use. Please review and adhere to our Terms and Conditions before ordering.