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LL-37

LL-37

LL-37, also known as Human Cathelicidin Antimicrobial Peptide (CAMP), is touted as a “mammal’s core tool” to fight off various harmful microorganisms in the body. It’s produced by many cell types including natural killer (NK) cells, white blood cells, and skin cells. In addition, different body systems such as the respiratory system, gastrointestinal tract, testes, and ocular surface also produce LL-37. This powerful peptide has piqued the interest of the research community because its immune-modulating activities have the potential to accelerate tissue recovery and significantly improve the survival rate of patients with chronic debilitating medical conditions.

Overall Health Benefits of LL-37

  • Significantly boosts immune function [1-15]
  • Fights inflammation [16-24]
  • Prevents cancer progression [25-54]
  • Accelerates wound healing [55-62]
  • Lowers risk of heart disease [63-65]
  • Prevents lung injury [66-67]
  • Promotes bone repair [68-72]

Proven Health Benefits of LL-37

Significantly Boosts Immune Function

An overwhelming body of research shows that this antimicrobial peptide regulates various important mechanisms involved in immune function:

  1. LL-37 boosts immune function by limiting the damage caused by bacterial products and recruiting immune cells to the site of infection. [1]
  2. A cell study found that LL-37 has the ability to inhibit the formation of bacterial biofilms (densely packed communities of microbial cells). [2]
  3. A cell study also found that LL-37 may help enhance the immunomodulatory function of human placenta-derived MSCs (pMSCs). [3]
  4. A study found that LL-37 was deadly against Staphylococcus aureus, the most common cause of upper respiratory tract infections. [4]
  5. LL-37 demonstrated strong antimicrobial activity against eye pathogens (infectious microorganisms). [5]
  6. Studies show LL-37 destroys harmful microorganisms by inducing programmed cell death (apoptosis). [6-8]
  7. A study found that LL-37 can kill a broad spectrum of bacteria. [9-10]
  8. LL-37 boosts immune response by attracting immune cells including T cells, monocytes, neutrophils, and mast cells to the site of infection. [11-12]
  9. LL-37 also affects the maturation of dendritic cells (antigen-presenting cells). [13]
  10. LL-37 stimulates the production of immune cells such as cytokines, chemokines, and their receptors. [14-15]
  11. Higher blood levels of LL-37 were associated with lower risk of death from infection in dialysis patients. [16]

Fights Inflammation

Aside from its immune-boosting properties, LL-37 also has potent anti-inflammatory activity according to high quality studies:

  1. In patients who had surgical removal of the tonsils, those with high levels of LL-37 had lesser inflammation compared to those with low LL-37. [17]
  2. LL-37 suppresses the translocation of NF-kB to the nucleus, which creates an anti-inflammatory effect. [18]
  3. In mice, LL-37 administration reduced the risk of inflammatory disease. [19]
  4. LL-37 reduces inflammation by modulating inflammatory pathways in the body. [20-22]
  5. In human gum cells, LL-37 strongly reduced the levels of pro-inflammatory cytokines and chemokines. [23]
  6. LL-37 also modulates the inflammatory and host defense response of human white blood cells. [24]

Prevents Cancer Progression

Studies show that LL-37 can help ward off deadly cancers:

  1. A cell study found that LL-37 has the potential to suppress cancer growth. [25]
  2. In another cell study, LL-37 suppressed the growth of colon cancer by inducing programmed cell death. [26]
  3. A study found that LL-37 has an anti-cancer effect in colon cancer, gastric cancer, skin cancer, ovarian cancer, lung cancer, breast cancer, prostate cancer, hematologic malignancy and oral cancer. [27]
  4. In various human cancer cell lines, LL-37 exhibited anti-cancer effect similar to chemotherapeutic drugs. [28]
  5. In human lung cancer cell line, LL-37 suppressed cancer progression by reducing the production of pro-inflammatory cytokines. [29]
  6. Cell studies have shown that LL-37 can inhibit migration and invasiveness of prostate cancer cells. [30-35]
  7. In colon cancer, gastric cancer, and skin cancer cell lines, treatment with LL-37 prevented cancer cell progression. [36-41]
  8. In colon cancer cell lines, LL-37 destroyed cancer cells by stimulating signaling pathways involved in programmed cell death. [42-46]
  9. In gastric cancer cell lines, LL-37 inhibited gastric cancer cell proliferation through activation of signaling pathways involved in cell cycle arrest. [47-50]
  10. In leukemic cell lines, recombinant LL-37 treatment killed malignant cells by activating programmed cell death. [51-52]
  11. In human oral cancer cell lines, treatment with LL-37 destroyed malignant cells by damaging their DNA. [53-54]

Accelerates Wound Healing

Studies also show that this peptide can help stimulate faster regeneration of wounds:

  1. In patients with venous leg ulcers, LL-37 treatment was associated with faster healing rate (almost six-fold higher) compared to placebo. [55]
  2. In mice, LL-37 treatment promoted wound healing through production of new blood vessels. [56]
  3. A cell study found that LL-37 induces wound healing by stimulating the proliferation and migration of cells necessary for regeneration. [57]
  4. In mice, LL-37 treatment improved re-epithelialization and granulation tissue formation – both of these processes are necessary for wound healing. [58-59]
  5. Cell studies found that LL-37 improves wound healing through its antimicrobial activity. [60-61]
  6. In patients with venous leg ulcers, low-dose LL-37 treatment markedly decreased the mean ulcer area. [62]

Lowers Risk of Heart Disease

LL-37 has also been found to possess cardioprotective effects:

  1. A study showed that LL-37 can protect against atherosclerosis (plaque build-up within the heart arteries). [63]
  2. A study also found that that LL-37 inhibited cell death in the heart, suggesting that increasing its level might have therapeutic benefits against heart failure. [64]
  3. In mice, heart failure was associated with the decrease in LL-37 levels and this deficiency worsened the condition. [65]

Prevents Lung Injury

Studies found that LL-37 is essential for healthy lungs:

  1. In mice, LL-37 attenuated the progression of lung injury by controlling inflammation and preventing infection. [66]
  2. A study reported that LL-37 is an effective inflammatory regulator in various lung diseases. [67]

Promotes Bone Repair

Evidence also suggests that LL-37 is vital for bone repair:

  1. A mice study found that LL-37-treated white blood cells promoted bone formation. [68]
  2. Cell studies also found that LL-37 can help prevent bone disorders by inhibiting bone breakdown. [69-70]
  3. In rats with bone defects, LL-37 treatment markedly induced newly formed bones. [71]
  4. A cell study reported that LL-37 induced bone formation by recruiting stem cells into the site of injury. [72]

References:

  1. Scott MG, Davidson DJ, Gold MR, Bowdish D, Hancock RE. The human antimicrobial peptide LL-37 is a multifunctional modulator of innate immune responses. J Immunol. 2002;169(7):3883-91.
  2. Overhage J, Campisano A, Bains M, Torfs EC, Rehm BH, Hancock RE. Human host defense peptide LL-37 prevents bacterial biofilm formation. Infect Immun. 2008;76(9):4176-82.
  3. Oliveira-Bravo M, Sangiorgi BB, Schiavinato JL, et al. LL-37 boosts immunosuppressive function of placenta-derived mesenchymal stromal cells. Stem Cell Res Ther. 2016;7(1):189. Published 2016 Dec 30. doi:10.1186/s13287-016-0448-3.
  4. Abou alaiwa MH, Reznikov LR, Gansemer ND, et al. pH modulates the activity and synergism of the airway surface liquid antimicrobials β-defensin-3 and LL-37. Proc Natl Acad Sci USA. 2014;111(52):18703-8.
  5. Huang LC, Petkova TD, Reins RY, Proske RJ, Mcdermott AM. Multifunctional roles of human cathelicidin (LL-37) at the ocular surface. Invest Ophthalmol Vis Sci. 2006;47(6):2369-80.
  6. De yang, Chen Q, Schmidt AP, et al. LL-37, the neutrophil granule- and epithelial cell-derived cathelicidin, utilizes formyl peptide receptor-like 1 (FPRL1) as a receptor to chemoattract human peripheral blood neutrophils, monocytes, and T cells. J Exp Med. 2000;192(7):1069-74.
  7. Yeaman MR, Yount NY. Mechanisms of antimicrobial peptide action and resistance. Pharmacol Rev. 2003;55(1):27-55.
  8. Cassagnes LE, Hervé V, Nepveu F, Hureau C, Faller P, Collin F. The catalytically active copper-amyloid-Beta state: coordination site responsible for reactive oxygen species production. Angew Chem Int Ed Engl. 2013;52(42):11110-3.
  9. Dürr UHN, Sudheendra US, Ramamoorthy A. LL-37, the only human member of the cathelicidin family of antimicrobial peptides. Biochim Biophys Acta. 2006 Sep;1758:1408–1425.
  10. Duplantier AJ, van Hoek ML. The Human Cathelicidin Antimicrobial Peptide LL-37 as a Potential Treatment for Polymicrobial Infected Wounds. Front Immunol. 2013;4:143.
  11. De Yang, Chen Q, Schmidt AP, Anderson GM, Wang JM, Wooters J, et al. LL-37, the neutrophil granule- and epithelial cell-derived cathelicidin, utilizes formyl peptide receptor-like 1 (FPRL1) as a receptor to chemoattract human peripheral blood neutrophils, monocytes, and T cells. J Exp Med. 2000 Oct 2;192:1069–1074.
  12. Niyonsaba F, Iwabuchi K, Someya A, Hirata M, Matsuda H, Ogawa H, et al. A cathelicidin family of human antibacterial peptide LL-37 induces mast cell chemotaxis. Immunology. 2002 May;106:20–26.
  13. Davidson DJ, Currie AJ, Reid GSD, Bowdish DME, MacDonald KL, Ma RC, et al. The cationic antimicrobial peptide LL-37 modulates dendritic cell differentiation and dendritic cell-induced T cell polarization. J Immunol Baltim Md 1950. 2004 Jan 15;172:1146–1156.
  14. Pistolic J, Cosseau C, Li Y, Yu JJ, Filewod NCJ, Gellatly S, et al. Host defence peptide LL-37 induces IL-6 expression in human bronchial epithelial cells by activation of the NF-kappaB signaling pathway. J Innate Immun. 2009;1:254–267.
  15. Montreekachon P, Chotjumlong P, Bolscher JGM, Nazmi K, Reutrakul V, Krisanaprakornkit S. Involvement of P2X(7) purinergic receptor and MEK1/2 in interleukin-8 up-regulation by LL-37 in human gingival fibroblasts. J Periodontal Res. 2011 Jun;46:327–337.
  16. Gombart AF, Bhan I, Borregaard N, et al. Low plasma level of cathelicidin antimicrobial peptide (hCAP18) predicts increased infectious disease mortality in patients undergoing hemodialysis. Clin Infect Dis. 2009;48(4):418-24.
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  19. Pancreatic β-Cells Limit Autoimmune Diabetes via an Immunoregulatory Antimicrobial Peptide Expressed under the Influence of the Gut Microbiota. Sun J, Furio L, Mecheri R, van der Does AM, Lundeberg E, Saveanu L, Chen Y, van Endert P, Agerberth B, Diana J. Immunity. 2015 Aug 18;43(2):304-17.
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  23. Jönsson D, Nilsson BO. The antimicrobial peptide LL-37 is anti-inflammatory and proapoptotic in human periodontal ligament cells. J Periodont Res. 2012;47(3):330-5.
  24. Alalwani SM, Sierigk J, Herr C, et al. The antimicrobial peptide LL-37 modulates the inflammatory and host defense response of human neutrophils. Eur J Immunol. 2010;40(4):1118–1126. doi:10.1002/eji.200939275.
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  43. Tuomela JM, Sandholm JA, Kaakinen M, Hayden KL, Haapasaari KM, Jukkola-Vuorinen A, Kauppila JH, Lehenkari PP, Harris KW, Graves DE, Selander KS: Telomeric G-quadruplex-forming DNA fragments induce TLR9-mediated and LL-37-regulated invasion in breast cancer cells in vitro. Breast Cancer Res Treat 2016; 155: 261-271.
  44. Ren SX, Cheng AS, To KF, Tong JH, Li MS, Shen J, Wong CC, Zhang L, Chan RL, Wang XJ, Ng SS, Chiu LC, Marquez VE, Gallo RL, Chan FK, Yu J, Sung JJ, Wu WK, Cho CH: Host immune defense peptide LL-37 activates caspase-independent apoptosis and suppresses colon cancer. Cancer Res 2012; 72: 6512-6523.
  45. Niemirowicz K, Prokop I, Wilczewska AZ, Wnorowska U, Piktel E, Wątek M, Savage PB, Bucki R: Magnetic nanoparticles enhance the anti-cancer activity of cathelicidin LL-37 peptide against colon cancer cells. Int J Nanomedicine 2015; 10: 3843-3853.
  46. Niemirowicz K, Durnaś B, Tokajuk G, Piktel E, Michalak G, Gu X, Kułakowska A, Savage PB, Bucki R: Formulation and candidacidal activity of magnetic nanoparticles coated with cathelicidin LL-37 and ceragenin CSA-13. Sci Rep 2017; 7: 4610.
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