Journal articles: 'LL-37'

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Schauber, J., T. Ruzicka, and R. A. Rupec. "Cathelicidin LL-37." Der Hautarzt 59, no. 1 (December 23, 2007): 72–74. http://dx.doi.org/10.1007/s00105-007-1457-z.

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Tripathi, Shweta, Tesfaldet Tecle, Anamika Verma, Erika Crouch, Mitchell White, and Kevan L. Hartshorn. "The human cathelicidin LL-37 inhibits influenza A viruses through a mechanism distinct from that of surfactant protein D or defensins." Journal of General Virology 94, no. 1 (January 1, 2013): 40–49. http://dx.doi.org/10.1099/vir.0.045013-0.

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LL-37, the only human cathelicidin, is a cationic antimicrobial peptide with antibacterial and antifungal activity. LL-37 is released from neutrophil granules and produced by epithelial cells. It has been implicated in host defence against influenza A virus (IAV) in recent studies. We now demonstrate dose-related neutralizing activity of LL-37 against several seasonal and mouse-adapted IAV strains. The ability of LL-37 to inhibit these IAV strains resulted mainly from direct effects on the virus, since pre-incubation of virus with LL-37 was needed for optimal inhibition. LL-37 bound high-density lipoprotein (HDL), and pre-incubation of LL-37 with human serum or HDL reduced its antiviral activity. LL-37 did not inhibit viral association with epithelial cells as assessed by quantitative RT-PCR or confocal microscopy. This finding contrasted with results obtained with surfactant protein D (SP-D). Unlike collectins or human neutrophil defensins (HNPs), LL-37 did not induce viral aggregation under electron microscopy. In the electron microscopy studies, LL-37 appeared to cause disruption of viral membranes. LL-37 had additive antiviral activity when combined with other innate inhibitors like SP-D, surfactant protein A and HNPs. Unlike HNPs, LL-37 did not bind SP-D significantly. These findings indicate that LL-37 contributes to host defence against IAV through a mechanism distinct from that of SP-D and HNPs.

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Rosen, Graciela, Michael N. Sela, and Gilad Bachrach. "The Antibacterial Activity of LL-37 against Treponema denticola Is Dentilisin Protease Independent and Facilitated by the Major Outer Sheath Protein Virulence Factor." Infection and Immunity 80, no. 3 (December 19, 2011): 1107–14. http://dx.doi.org/10.1128/iai.05903-11.

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Host defense peptides are innate immune effectors that possess both bactericidal activities and immunomodulatory functions. Deficiency in the human host defense peptide LL-37 has previously been correlated with severe periodontal disease.Treponema denticolais an oral anaerobic spirochete closely associated with the pathogenesis of periodontal disease. TheT. denticolamajor surface protein (MSP), involved in adhesion and cytotoxicity, and the dentilisin serine protease are key virulence factors of this organism. In this study, we examined the interactions between LL-37 andT. denticola. The threeT. denticolastrains tested were susceptible to LL-37. Dentilisin was found to inactivate LL-37 by cleaving it at the Lys, Phe, Gln, and Val residues. However, dentilisin deletion did not increase the susceptibility ofT. denticolato LL-37. Furthermore, dentilisin activity was found to be inhibited by human saliva. In contrast, a deficiency of theT. denticolaMSP increased resistance to LL-37. The MSP-deficient mutant bound less fluorescently labeled LL-37 than the wild-type strain. MSP demonstrated specific, dose-dependent LL-37 binding. In conclusion, though capable of LL-37 inactivation, dentilisin does not protectT. denticolafrom LL-37. Rather, the rapid, MSP-mediated binding of LL-37 to the treponemal outer sheath precedes cleavage by dentilisin. Moreover,in vivo, saliva inhibits dentilisin, thus preventing LL-37 restriction and ensuring its bactericidal and immunoregulatory activities.

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Bryzek, Danuta, Anna Golda, Joanna Budziaszek, Dominik Kowalczyk, Alicia Wong, Ewa Bielecka, Priyanka Shakamuri, et al. "Citrullination-Resistant LL-37 Is a Potent Antimicrobial Agent in the Inflammatory Environment High in Arginine Deiminase Activity." International Journal of Molecular Sciences 21, no. 23 (November 30, 2020): 9126. http://dx.doi.org/10.3390/ijms21239126.

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LL-37, the only member of the mammalian cathelicidin in humans, plays an essential role in innate immunity by killing pathogens and regulating the inflammatory response. However, at an inflammatory focus, arginine residues in LL-37 can be converted to citrulline via a reaction catalyzed by peptidyl-arginine deiminases (PAD2 and PAD4), which are expressed in neutrophils and are highly active during the formation of neutrophil extracellular traps (NETs). Citrullination impairs the bactericidal activity of LL-37 and abrogates its immunomodulatory functions. Therefore, we hypothesized that citrullination-resistant LL-37 variants would retain the functionality of the native peptide in the presence of PADs. To test this hypothesis, we synthetized LL-37 in which arginine residues were substituted by homoarginine (hArg-LL-37). Bactericidal activity of hArg-LL-37 was comparable with that of native LL-37, but neither treatment with PAD4 nor exposure to NETs affected the antibacterial and immunomodulatory activities of hArg-LL-37. Importantly, the susceptibilities of LL-37 and hArg-LL-37 to degradation by proteases did not significantly differ. Collectively, we demonstrated that citrullination-resistant hArg-LL-37 is an attractive lead compound for the generation of new agents to treat bacterial infections and other inflammatory diseases associated with enhanced PAD activity. Moreover, our results provide a proof-of-concept for synthesis of therapeutic peptides using homoarginine.

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Zhao, Chengquan, Tung Nguyen, Lee Ming Boo, Teresa Hong, Cesar Espiritu, Dmitri Orlov, Wei Wang, Alan Waring, and Robert I. Lehrer. "RL-37, an Alpha-Helical Antimicrobial Peptide of the Rhesus Monkey." Antimicrobial Agents and Chemotherapy 45, no. 10 (October 1, 2001): 2695–702. http://dx.doi.org/10.1128/aac.45.10.2695-2702.2001.

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ABSTRACT Rhesus monkey bone marrow expresses a cathelicidin whose C-terminal domain comprises a 37-residue alpha-helical peptide (RL-37) that resembles human LL-37. Like its human counterpart, RL-37 rapidly permeabilized the membranes of Escherichia coli ML-35p and lysed liposomes that simulated bacterial membranes. When tested in media whose NaCl concentrations approximated those of extracellular fluids, RL-37 was considerably more active than LL-37 against staphylococci. Whereas human LL-37 contains five acidic residues and has a net charge of +6, rhesus RL-37 has only two acidic residues and a net charge of +8. Speculating that the multiple acidic residues of human LL-37 reduced its efficacy against staphylococci, we made a peptide (LL-37 pentamide) in which each aspartic acid of LL-37 was replaced by an asparagine and each glutamic acid was replaced by a glutamine. LL-37 pentamide's antistaphylococcal activity was substantially greater than that of LL-37. Thus, although the precursor of LL-37 is induced in human skin keratinocytes by injury or inflammation, its insufficiently cationic antimicrobial domain may contribute to the success of staphylococci in colonizing and infecting human skin.

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Rapala-Kozik, Maria, Oliwia Bochenska, Marcin Zawrotniak, Natalia Wolak, Grzegorz Trebacz, Mariusz Gogol, Dominika Ostrowska, Wataru Aoki, Mitsuyoshi Ueda, and Andrzej Kozik. "Inactivation of the Antifungal and Immunomodulatory Properties of Human Cathelicidin LL-37 by Aspartic Proteases Produced by the Pathogenic Yeast Candida albicans." Infection and Immunity 83, no. 6 (April 6, 2015): 2518–30. http://dx.doi.org/10.1128/iai.00023-15.

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Constant cross talk betweenCandida albicansyeast cells and their human host determines the outcome of fungal colonization and, eventually, the progress of infectious disease (candidiasis). An effective weapon used byC. albicansto cope with the host defense system is the release of 10 distinct secreted aspartic proteases (SAPs). Here, we validate a hypothesis that neutrophils and epithelial cells use the antimicrobial peptide LL-37 to inactivateC. albicansat sites of candidal infection and thatC. albicansuses SAPs to effectively degrade LL-37. LL-37 is cleaved into multiple products by SAP1 to -4, SAP8, and SAP9, and this proteolytic processing is correlated with the gradual decrease in the antifungal activity of LL-37. Moreover, a major intermediate of LL-37 cleavage—the LL-25 peptide—is antifungal but devoid of the immunomodulatory properties of LL-37. In contrast to LL-37, LL-25 did not affect the generation of reactive oxygen species by neutrophils upon treatment with phorbol esters. Stimulating neutrophils with LL-25 (rather than LL-37) significantly decreased calcium flux and interleukin-8 production, resulting in lower chemotactic activity of the peptide against neutrophils, which may decrease the recruitment of neutrophils to infection foci. LL-25 also lost the function of LL-37 as an inhibitor of neutrophil apoptosis, thereby reducing the life span of these defense cells. This study indicates thatC. albicanscan effectively use aspartic proteases to destroy the antimicrobial and immunomodulatory properties of LL-37, thus enabling the pathogen to survive and propagate.

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Honda, Jennifer R., Elizabeth Connick, Samantha MaWhinney, Edward D. Chan, and Sonia C. Flores. "Plasma LL-37 correlates with vitamin D and is reduced in human immunodeficiency virus-1 infected individuals not receiving antiretroviral therapy." Journal of Medical Microbiology 63, no. 7 (July 1, 2014): 997–1003. http://dx.doi.org/10.1099/jmm.0.070888-0.

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Low levels of the vitamin D-regulated antimicrobial peptide cathelicidin (LL-37) may negatively impact the immune status of human immunodeficiency virus-1 (HIV-1) infected individuals (HIV+). We compared plasma LL-37 levels in healthy controls (HIV−) and HIV+ individuals on or off antiretroviral therapies (ARTs) (ART+ and ART−, respectively), and evaluated the relationship between vitamin D and LL-37 levels. In this cross-sectional study, levels of LL-37, 25-hydroxycholecalciferol [25(OH)D3] and 1,25-dihydroxycholecalciferol [1,25(OH)2D3] were measured from an initial cohort of 18 healthy controls and 10 HIV+/ART− individuals. Because this cohort lacked HIV+/ART+ subjects, LL-37 was also quantified from a second cohort of 10 HIV+/ART− and 13 HIV+/ART+ individuals. LL-37 levels were significantly lower in the HIV+/ART− group compared to the healthy controls (P = 0.01). A direct relationship was observed between LL-37 and both 25(OH)D3 and 1,25(OH)2D3. The level of 25(OH)D3 was predictive of higher LL-37 (P = 0.04) and for any given level of 25(OH)D3, HIV+/ART− subjects averaged 20 % lower LL-37 compared to the healthy controls (P = 0.045). For any given level of 1,25(OH)2D3, HIV+/ART− subjects averaged 25 % lower LL-37 compared to the healthy controls (P = 0.018), although 1,25(OH)2D3 was not predictive of higher LL-37 (P = 0.28). Finally, LL-37 levels were significantly lower in the HIV+/ART− group compared to the HIV+/ART+ group from the second cohort (P = 0.045). Untreated HIV infection may contribute to lower LL-37 levels, independent of vitamin D levels. ART treatment may potentially mitigate this decrease in LL-37 levels.

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Sigurdardottir, Thorgerdur, Pia Andersson, Mina Davoudi, Martin Malmsten, Artur Schmidtchen, and Mikael Bodelsson. "In Silico Identification and Biological Evaluation of Antimicrobial Peptides Based on Human Cathelicidin LL-37." Antimicrobial Agents and Chemotherapy 50, no. 9 (September 2006): 2983–89. http://dx.doi.org/10.1128/aac.01583-05.

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ABSTRACT Bacterial lipopolysaccharides (LPS) are important triggers of the widespread inflammatory response, which contributes to the development of multiple organ failure during sepsis. The helical 37-amino-acid-long human antimicrobial peptide LL-37 not only possesses a broad-spectrum antimicrobial activity but also binds and neutralizes LPS. However, the use of LL-37 in sepsis treatment is hampered by the fact that it is also cytotoxic. To find a less toxic analog of LL-37, we used in silico analysis to identify amphipathic helical regions of LL-37. A 21-amino-acid fragment (GKE) was synthesized, the biological actions of which were compared to those of two equally long peptides derived from the N and C termini of LL-37 as well as native LL-37. GKE displayed antimicrobial activity against Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Candida albicans, and Candida parapsilosis that was similar to or even stronger than LL-37. GKE, as well as the equally long control peptides, attracted granulocytes in a fashion similar to that of LL-37, while only GKE was as potent as LL-37 in inhibiting LPS-induced vascular nitric oxide production. GKE caused less hemolysis and apoptosis in human cultured smooth muscle cells than LL-37. In summary, we have identified an active domain of LL-37, GKE, which displays antimicrobial activity in vitro and LPS-binding activity similar to those of LL-37 but is less toxic. GKE therefore holds promise as a template for the development of peptide antibiotics for the treatment of sepsis.

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Sieprawska-Lupa, Magdalena, Piotr Mydel, Katarzyna Krawczyk, Kinga Wójcik, Magdalena Puklo, Boguslaw Lupa, Piotr Suder, et al. "Degradation of Human Antimicrobial Peptide LL-37 by Staphylococcus aureus-Derived Proteinases." Antimicrobial Agents and Chemotherapy 48, no. 12 (December 2004): 4673–79. http://dx.doi.org/10.1128/aac.48.12.4673-4679.2004.

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ABSTRACT Cathelicidin LL-37 is one of the few human bactericidal peptides with potent antistaphylococcal activity. In this study we examined the susceptibility of LL-37 to proteolytic degradation by two major proteinases produced by Staphylococcus aureus, a metalloproteinase (aureolysin) and a glutamylendopeptidase (V8 protease). We found that aureolysin cleaved and inactivated LL-37 in a time- and concentration-dependent manner. Analysis of the generated fragments by mass spectroscopy revealed that the initial cleavage of LL-37 by aureolysin occurred between the Arg19-Ile20, Arg23-Ile24, and Leu31-Val32 peptide bonds, instantly annihilating the antibacterial activity of LL-37. In contrast, the V8 proteinase hydrolyzed efficiently only the Glu16-Phe17 peptide bond, rendering the C-terminal fragment refractory to further degradation. This fragment (termed LL-17-37) displayed antibacterial activity against S. aureus at a molar level similar to that of the full-length LL-37 peptide, indicating that the antibacterial activity of LL-37 resides in the C-terminal region. In keeping with LL-37 degradation by aureolysin, S. aureus strains that produce significant amounts of this metalloprotease were found to be less susceptible to LL-17-37 than strains expressing no aureolysin activity. Taken together, these data suggest that aureolysin production by S. aureus contributes to the resistance of this pathogen to the innate immune system of humans mediated by LL-37.

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Ohuchi, Kentaro, Tetsuya Ikawa, Ryo Amagai, Toshiya Takahashi, Yuna Roh, Junko Endo, Yumi Kambayashi, Yoshihide Asano, and Taku Fujimura. "LL-37 Might Promote Local Invasion of Melanoma by Activating Melanoma Cells and Tumor-Associated Macrophages." Cancers 15, no. 6 (March 9, 2023): 1678. http://dx.doi.org/10.3390/cancers15061678.

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LL-37 can stimulate various skin-resident cells to contribute to tumor development. Since tumor (T) stage is determined by the vertical invasion of tumor cells in melanoma, we hypothesized that the LL-37 expression level is correlated with the T stage in melanoma patients. Immunohistochemical staining of LL-37 was performed in each stage of melanoma (Tis-T4), suggesting the ratio of LL-37-expressing cells correlate positively to T stage severity. Next, to examine pro-angiogenetic factors induced by LL-37 stimulation, the B16F10 melanoma model was used. Intra-tumorally administered CRAMP, the mouse ortologe of LL-37, significantly increased the mRNA expression of CXCL5, IL23A, MMP1a, and MMP9 in B16F10 melanoma. To confirm the induction of pro-angiogenic factors, A375 human melanoma cells were stimulated by LL-37 in vitro. The mRNA expression of CXCL5, IL23A, and MMP9, but not MMP1, were significantly increased by LL-37 stimulation. Moreover, LL-37-stimulated A375 culture supernatant promoted tube networks, suggesting that these tumor-derived factors promote the pro-angiogenic effect on tumor development. In contrast to melanoma cell lines, M2 macrophages stimulated by LL-37 in vitro significantly increased their expression and secretion of MMP-1, but not MMP-9 expression. Collectively, these results suggest that LL-37 stimulates both tumor cells and macrophages to promote melanoma invasion by the induction of pro-angiogenic factors.

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Torossian, Alexander, Eugeniu Gurschi, Robert Bals, Timon Vassiliou, Hinnerk F. Wulf, and Artur Bauhofer. "Effects of the Antimicrobial Peptide LL-37 and Hyperthermic Preconditioning in Septic Rats." Anesthesiology 107, no. 3 (September 1, 2007): 437–41. http://dx.doi.org/10.1097/01.anes.0000278906.86815.eb.

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Background The authors tested the effects of LL-37 prophylaxis or therapy on the outcome after intraabdominal sepsis and examined whether hyperthermic preconditioning plus LL-37 therapy augments host immune response and improves survival. Methods A rat model of peritoneal contamination and infection (PCI) with human stool was used to simulate clinical conditions. In trial 1, the authors compared (1) PCI, (2) LL-37 prophylaxis (0.5 mg/kg, 12 h before PCI), and (3) LL-37 therapy (0.5 mg/kg, 1 h after PCI). In trial 2, the authors compared (1) PCI, (2) LL-37 therapy, (3) hyperthermic preconditioning (41 degrees C for 1 h, 24 h before PCI), and (4) LL-37 therapy and hyperthermic preconditioning. The primary endpoint was mortality at 120 h. In trial 2, secondary endpoints were systemic levels of tumor necrosis factor alpha, interleukin 6, macrophage inflammatory protein 2, and heat shock protein 70; leukocyte counts; and neutrophil granulocyte phagocytosis. Results In trial 1, 30% of the control group compared with 70% of the LL-37 therapy group survived, but 55% after LL-37 prophylaxis survived (P = 0.038). In trial 2, 38% of the controls, 67% of the LL-37 therapy, 59% of the hyperthermic preconditioned, and 90% of the hyperthermic preconditioned plus LL-37 therapy group survived (P = 0.01). LL-37 therapy plus hyperthermic preconditioning reduced proinflammatory cytokine concentrations after sepsis; specifically compared with controls, macrophage inflammatory protein-2 and interleukin-6 levels were 1.5 +/- 1.5 versus 11 +/- 6 pg/ml (P = 0.028) and 13 +/- 8 versus 86 +/- 31 pg/ml, (P = 0.015), respectively. Conclusions In this model of intraabdominal sepsis, LL-37 therapy improved outcome. Hyperthermic preconditioning per se was not successful, but in combination with LL-37 therapy, the survival rate after sepsis was increased and the proinflammatory cytokine response was downgraded.

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Kumagai, Yumi, Taisuke Murakami, Kuwahara-Arai, Toshiaki Iba, Johannes Reich, and Isao Nagaoka. "Antimicrobial peptide LL-37 ameliorates a murine sepsis model via the induction of microvesicle release from neutrophils." Innate Immunity 26, no. 7 (June 29, 2020): 565–79. http://dx.doi.org/10.1177/1753425920936754.

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Sepsis is a life-threatening disease caused by systemic dys-regulated inflammatory response to infection. We previously revealed that LL-37, a human cathelicidin antimicrobial peptide, improves the survival of cecal ligation and puncture septic mice. Ectosomes, microvesicles released from neutrophils, are reported to be elevated in sepsis survivors; however, the functions of ectosomes in sepsis remain largely unknown. Therefore, we herein elucidated the protective action of LL-37 on sepsis, by focusing on LL-37-induced ectosome release in a cecal ligation and puncture model. The results demonstrated the enhancement of ectosome levels by LL-37 administration, accompanied by a reduction of bacterial load. Importantly, ectosomes isolated from LL-37-injected cecal ligation and puncture mice contained higher amounts of antimicrobial proteins/peptides and exhibited higher antibacterial activity, compared with those from PBS-injected cecal ligation and puncture mice, suggesting that LL-37 induces the release of ectosomes with antibacterial potential in vivo. Actually, LL-37 stimulated mouse bone-marrow neutrophils to release ectosomes ex vivo, and the LL-37-induced ectosomes possessed antibacterial potential. Furthermore, administration of LL-37-induced ectosomes reduced the bacterial load and improved the survival of cecal ligation and puncture mice. Together these observations suggest LL-37 induces the release of antimicrobial ectosomes in cecal ligation and puncture mice, thereby reducing the bacterial load and protecting mice from lethal septic conditions.

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Uhlmann, Julia, Manfred Rohde, Nikolai Siemens, Bernd Kreikemeyer, Peter Bergman, Linda Johansson, and Anna Norrby-Teglund. "LL-37 Triggers Formation of Streptococcus pyogenes Extracellular Vesicle-Like Structures with Immune Stimulatory Properties." Journal of Innate Immunity 8, no. 3 (December 8, 2015): 243–57. http://dx.doi.org/10.1159/000441896.

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Reports have shown that the antimicrobial peptide LL-37 is abundantly expressed but has limited bactericidal effect in Streptococcus pyogenes infections. At sub-inhibitory concentrations, LL-37 has been reported to alter virulence gene expression. Here, we explored the interaction of S. pyogenes strains with LL-37, focusing on bacterial growth, cell surface alterations and pro-inflammatory responses. Bioscreen turbidity measurements of strain 5448 cultured in the presence or absence of LL-37 confirmed the poor antimicrobial effect, and revealed a significant increase in turbidity of bacterial cultures exposed to sub-inhibitory concentrations of LL-37. However, this was not linked to increased bacterial counts. Electron microscopy of LL-37-exposed bacteria revealed the presence of vesicle-like structures on the bacterial surface. The vesicles stained positive for LL-37 and were released from the bacterial surface. Concentrated supernatants enriched in these structures had a broader protein content, including several virulence factors, compared to supernatants from untreated bacteria. The supernatants from LL-37-exposed bacteria were pro-inflammatory and elicited resistin and myeloperoxidase release from neutrophils. This is the first report on S. pyogenes extracellular vesicle-like structures formed at the bacterial surface in response to LL-37. The associated increased pro-inflammatory activity further implicates LL-37 as a potential factor involved in S. pyogenes pathogenesis.

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Yusuf, Muhammad, Wanda Destiarani, Ade Rizqi Ridwan Firdaus, Fauzian Giansyah Rohmatulloh, Mia Tria Novianti, Gita Widya Pradini, and Reiva Farah Dwiyana. "Residual Interactions of LL-37 with POPC and POPE:POPG Bilayer Model Studied by All-Atom Molecular Dynamics Simulation." International Journal of Molecular Sciences 23, no. 21 (November 2, 2022): 13413. http://dx.doi.org/10.3390/ijms232113413.

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LL-37 is a membrane-active antimicrobial peptide (AMP) that could disrupt the integrity of bacterial membranes due to its inherent cationic and amphipathic nature. Developing a shorter derivative of a long peptide such as LL-37 is of great interest, as it can reduce production costs and cytotoxicity. However, more detailed information about the residual interaction between LL-37 and the membrane is required for further optimization. Previously, molecular dynamics simulation using mixed all-atom and united-atom force fields showed that LL-37 could penetrate the bilayer membrane. This study aimed to perform all-atom molecular dynamics simulations, highlighting the residual interaction of LL-37 with the simplest model of the bacterial membrane, POPE:POPG (2:1), and compare its interaction with the POPC, which represents the eukaryotic membrane. The result showed leucine–leucine as the leading residues of LL-37 that first contact the membrane surface. Then, the cationic peptide of LL-37 started to penetrate the membrane by developing salt bridges between positively charged amino acids, Lys–Arg, and the exposed phosphate group of POPE:POPG, which is shielded in POPC. Residues 18 to 29 are suggested as the core region of LL-37, as they actively interact with the POPE:POPG membrane, not POPC. These results could provide a basis for modifying the amino acid sequence of LL-37 and developing a more efficient design for LL-37 derivatives.

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Sahebari, M., G. Roshandel, N. Saadati, M. Saghafi, N. Abdolahi, and Z. Rezaieyazdi. "Cathelicidin (LL-37) and its correlation with pro-oxidant, antioxidant balance and disease activity in systemic lupus erythematosus: a cross-sectional human study." Lupus 26, no. 9 (March 17, 2017): 975–82. http://dx.doi.org/10.1177/0961203317691368.

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Background Cathelicidin (LL-37), an endogenous antimicrobial peptide, has recently been involved in the pathogenesis of autoimmune diseases. To assess whether LL-37 reflects disease activity, we measured serum levels of it in systemic lupus erythematosus (SLE) patients with active and inactive disease compared to healthy controls. LL-37 was also compared between new and old cases. Moreover, the correlation of LL-37 and pro-oxidant, antioxidant balance (PAB) was measured. Methods The study population consisted of 50 SLE patients and 28 healthy controls. Of those, 39 patients had active and 11 patients had inactive disease. Serum levels of LL-37 were measured by ELISA and PAB values by a special method. Results There was no difference in levels of LL-37 between patients and healthy controls (50.9 ± 20.8 vs. 67.7 ± 43.3 ng/ml, P = 0.31). LL-37 did not correlate with SLEDAI and its items in total patients. LL-37 had a positive correlation with SLEDAI in active patients ( P = 0.01, r = 0.4). In active patients (78% of patients), multivariate regression analysis showed significant negative correlation between LL-37 and C3 ( P = 0.01, standardized beta –0.50). No difference was found in levels of PAB between patients and controls (90.4 ± 34.1 vs. 86.9 ± 25.6 HK, P = 0.4).There was no difference in the levels of PAB between patients with active and inactive disease (93.2 ± 34.1 vs. 80.2 ± 33.7 HK, P = 0.27). No correlation was found between levels of PAB and SLEDAI items and total score. However, a positive correlation between the levels of LL-37 and PAB in SLE patients was found ( r = 0.3, P < 0.01). Conclusion Based on this study, serum LL-37 and PAB did not increase in lupus compared with healthy individuals. LL-37 serum values rose in parallel with SLEDAI in active disease. Positive correlation between serum PAB and LL-37 could be a great achievement of this study that may suggest the role of antioxidants in controlling NETosis.

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Lau, Y. Elaine, Annett Rozek, Monisha G. Scott, Danika L. Goosney, Donald J. Davidson, and Robert E. W. Hancock. "Interaction and Cellular Localization of the Human Host Defense Peptide LL-37 with Lung Epithelial Cells." Infection and Immunity 73, no. 1 (January 2005): 583–91. http://dx.doi.org/10.1128/iai.73.1.583-591.2005.

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ABSTRACT LL-37 is a human cationic host defense peptide that is an essential component of innate immunity. In addition to its modest antimicrobial activity, LL-37 affects the gene expression and behavior of effector cells involved in the innate immune response, although its mode of interaction with eukaryotic cells remains unclear. The interaction of LL-37 with epithelial cells was characterized in tissue culture by using biotinylated LL-37 and confocal microscopy. It was demonstrated that LL-37 was actively taken up into A549 epithelial cells and eventually localized to the perinuclear region. Specific inhibitors were used to demonstrate that the uptake process was not mediated by actin but required elements normally involved in endocytosis and that trafficking to the perinuclear region was dependent on microtubules. By using nonlinear regression analysis, it was revealed that A549 epithelial cells have two receptors for LL-37B, with high and low affinity for LL-37, respectively. These results indicate the mode of interaction of LL-37 with epithelial cells and further our understanding of its role in modulating the innate immune response.

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Jones, Allison, Miriam Geörg, Lisa Maudsdotter, and Ann-Beth Jonsson. "Endotoxin, Capsule, and Bacterial Attachment Contribute to Neisseria meningitidis Resistance to the Human Antimicrobial Peptide LL-37." Journal of Bacteriology 191, no. 12 (April 17, 2009): 3861–68. http://dx.doi.org/10.1128/jb.01313-08.

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ABSTRACT Pathogenic bacteria have evolved numerous mechanisms to evade the human immune system and have developed widespread resistance to traditional antibiotics. We studied the human pathogen Neisseria meningitidis and present evidence of novel mechanisms of resistance to the human antimicrobial peptide LL-37. We found that bacteria attached to host epithelial cells are resistant to 10 μM LL-37 whereas bacteria in solution or attached to plastic are killed, indicating that the cell microenvironment protects bacteria. The bacterial endotoxin lipooligosaccharide and the polysaccharide capsule contribute to LL-37 resistance, probably by preventing LL-37 from reaching the bacterial membrane, as more LL-37 reaches the bacterial membrane on both lipooligosaccharide-deficient and capsule-deficient mutants whereas both mutants are also more susceptible to LL-37 killing than the wild-type strain. N. meningitidis bacteria respond to sublethal doses of LL-37 and upregulate two of their capsule genes, siaC and siaD, which further results in upregulation of capsule biosynthesis.

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Byfield, Fitzroy J., Qi Wen, Katarzyna Leszczyńska, Alina Kułakowska, Zbigniew Namiot, Paul A. Janmey, and Robert Bucki. "Cathelicidin LL-37 peptide regulates endothelial cell stiffness and endothelial barrier permeability." American Journal of Physiology-Cell Physiology 300, no. 1 (January 2011): C105—C112. http://dx.doi.org/10.1152/ajpcell.00158.2010.

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LL-37 peptide is a multifunctional host defense molecule essential for normal immune responses to infection or tissue injury. In this study we assess the impact of LL-37 on endothelial stiffness and barrier permeability. Fluorescence microscopy reveals membrane localization of LL-37 after its incubation with human umbilical vein endothelial cells (HUVECs). A concentration-dependent increase in stiffness was observed in HUVECs, bovine aortic endothelial cells (BAECs), human pulmonary microvascular endothelial cells, and mouse aorta upon LL-37 (0.5–5 μM) addition. Stiffening of BAECs by LL-37 was blocked by P2X7 receptor antagonists and by the intracellular Ca2+ chelator BAPTA-AM. Increased cellular stiffness correlated with a decrease in permeability of HUVEC cell monolayers after LL-37 addition compared with nontreated cells, which was similar to the effect observed upon treatment with sphingosine 1-phosphate, and both treatments increased F-actin content in the cortical region of the cells. These results suggest that the antiinflammatory effect of LL-37 at the site of infection or injury involves an LL-37-mediated increase in cell stiffening that prevents increased pericellular permeability. Such a mechanism may help to maintain tissue fluid homeostasis.

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Gutner, Michal, Stella Chaushu, Daniela Balter, and Gilad Bachrach. "Saliva Enables the Antimicrobial Activity of LL-37 in the Presence of Proteases of Porphyromonas gingivalis." Infection and Immunity 77, no. 12 (October 5, 2009): 5558–63. http://dx.doi.org/10.1128/iai.00648-09.

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ABSTRACT Proteolysis is a common microbial virulence mechanism that enables the destruction of host tissue and evasion from host defense mechanisms. Antimicrobial peptides, also known as host defense peptides, are effector molecules of the innate immunity that demonstrate a broad range of antimicrobial and immunoregulatory activities. Deficiency of the human LL-37 antimicrobial peptide was previously correlated with severe periodontal disease. Porphyromonas gingivalis, the major pathogen associated with periodontitis, is highly proteolytic. In this study, P. gingivalis was found capable of degrading LL-37 by utilizing its arginine-specific gingipains. Saliva collected from volunteers with a healthy periodontium protected LL-37 from proteolysis by P. gingivalis. Salivary protection of LL-37 was heat resistant and specific and enabled LL-37 to inhibit growth of Escherichia coli in the presence of the P. gingivalis proteases. Previously, saliva and other body fluids have been shown to inhibit the antimicrobial activity of LL-37. Here we demonstrate that at a cost of a small reduction in the bactericidal activity of LL-37, saliva enables the antibacterial activity of LL-37 despite the presence of proteases secreted by the main periodontopathogen.

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Kim, Hee Jung, Jung Min Choi, Baik Kee Cho, Dae Ho Cho, and Hyun Jeong Park. "Vitamin C attenuates ERK signaling induced by LL-37 in human dermal fibroblasts (89.5)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 89.5. http://dx.doi.org/10.4049/jimmunol.184.supp.89.5.

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Abstract Vitamin C (ascorbic acid), a water-soluble micronutrient present in fruits and vegetables, is important for multiple biological functions. Vitamin C is used as an anti-aging agent because of its collagen enhancing effects. The precise cellular signaling mechanism of vitamin C is not well known. Here we investigate the profibrotic mechanism of vitamin C against LL-37. Antimicrobial peptide LL-37 decreases collagen expression at mRNA and protein levels in human dermal fibroblasts (HDFs). The ability of LL-37 to inhibit collagen expression is dependent on phosphorylation of extracellular signal-regulated kinase (ERK). HDFs were treated with vitamin C before 2 hours of LL-37 treatment. Vitamin C, at 0.5mM concentration, enhances collagen mRNA expression and total soluble collagen production inhibited by LL-37. H2O2 decreased the expression of COL1A1, COL1A2, and COL3A1 mRNA, as was collagen production. We found that collagen expression and production reduced by LL-37 were increased by N-acetyl-L-cysteine (NAC). These results indicate that ROI levels are involved in collagen expression. Furthermore, vitamin C turned off phosphorylation of ERK that was induced by LL-37. Ets-1 transcriptional factor, which is involved in the regulation of collagen expression by LL-37, was also inhibited by vitamin C. This study shows that vitamin C enhances collagen production by inhibiting the ERK pathway induced by LL-37.

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Amagai, Ryo, Toshiya Takahashi, Hitoshi Terui, Taku Fujimura, Kenshi Yamasaki, Setsuya Aiba, and Yoshihide Asano. "The Antimicrobial Peptide Cathelicidin Exerts Immunomodulatory Effects via Scavenger Receptors." International Journal of Molecular Sciences 24, no. 1 (January 3, 2023): 875. http://dx.doi.org/10.3390/ijms24010875.

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An active form of cathelicidin antimicrobial peptide, LL-37, has immunomodulatory and stimulatory effects, though the specific pathways are not clear. The purpose of this study was to identify the cellular pathways by which LL-37 amplifies the inflammation induced by damage-associated molecular patterns (DAMPs). We performed DNA microarray, reverse transcription polymerase chain reaction, immunoblotting, and proximity ligation assays using cultured keratinocytes treated with LL-37 and/or the DAMP poly(I:C), a synthetic double-stranded RNA. In contrast to the combination of LL-37 and poly(I:C), LL-37 alone induced genes related to biological metabolic processes such as VEGFA and PTGS2 (COX-2). Inhibition of FPR2, a known receptor for cathelicidin, partially suppressed the induction of VEGFA and PTGS2. Importantly, VEGFA and PTGS2 induced by LL-37 alone were diminished by the knockdown of scavenger receptors including SCARB1 (SR-B1), OLR1 (SR-E1), and AGER (SR-J1). Moreover, LL-37 alone, as well as the combination of LL-37 and poly(I:C), showed proximity to the scavenger receptors, indicating that LL-37 acts via scavenger receptors and intermediates between them and poly(I:C). These results showed that the broad function of cathelicidin is generally dependent on scavenger receptors. Therefore, inhibitors of scavenger receptors or non-functional mock cathelicidin peptides may serve as new anti-inflammatory and immunosuppressive agents.

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Chawla, Himika, Parmita Kar, Soma Saha, Urvashi B. Singh, Nikhil Tandon, and Goswami R. "Circulating Antimicrobial Peptide LL-37 Status in Type 1 Diabetes Mellitus and its Relation with Glycemic Control." Annals of the National Academy of Medical Sciences (India) 53, no. 02 (April 2017): 066–72. http://dx.doi.org/10.1055/s-0040-1712747.

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ABSTRACTAntimicrobial-peptides are important molecules of constitutive innate immunity. Though patients with diabetes mellitus are generally prone to infections, there is limited information on their antimicrobialpeptide status. We assessed the circulating LL-37 antimicrobial peptide (also referred as cathelicidin) levels in patients with type 1 diabetes mellitus and its relation with their glycemic status. The LL-37 mRNAexpression was assessed in the peripheral blood mononuclear cells (PBMC) by quantitative RTPCR using ß-actin and cytochrome-C1 as the reference genes in 154 subjects (Type 1 diabetes, n=111 and healthy subjects, n=43). Serum LL-37 was quantiﬁed using sandwich-ELISA. Average HbA1c over last 2 years and current HbA1c were used to determine long-term and short-term glycemic status. LL-37 mRNAexpression and serum LL-37 levels were correlated with the glycemic status. The LL-37 mRNA copies were comparable between type 1 diabetes and healthy subjects [median (IQR) = 6.7 (1.8–15.28) vs. 7.2 (2.23–21.86), respectively, P = 0.42]. There was no signiﬁcant difference in serum LL-37 levels between the two groups [median (IQR) = 3.9 (2.88–7.52) vs. 5.0 (3.19–9.05) ng/ml, respectively, P = 0.52]. The LL-37 mRNA and its protein concentration showed no signiﬁcant correlation with the average or current HbA1c values. The constitutive circulating antimicrobial peptide LL-37 status is not signiﬁcantly altered in patients with type 1 diabetes mellitus and also not affected by their glycemic status.

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Ridyard, Kylen E., and Joerg Overhage. "The Potential of Human Peptide LL-37 as an Antimicrobial and Anti-Biofilm Agent." Antibiotics 10, no. 6 (May 29, 2021): 650. http://dx.doi.org/10.3390/antibiotics10060650.

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The rise in antimicrobial resistant bacteria threatens the current methods utilized to treat bacterial infections. The development of novel therapeutic agents is crucial in avoiding a post-antibiotic era and the associated deaths from antibiotic resistant pathogens. The human antimicrobial peptide LL-37 has been considered as a potential alternative to conventional antibiotics as it displays broad spectrum antibacterial and anti-biofilm activities as well as immunomodulatory functions. While LL-37 has shown promising results, it has yet to receive regulatory approval as a peptide antibiotic. Despite the strong antimicrobial properties, LL-37 has several limitations including high cost, lower activity in physiological environments, susceptibility to proteolytic degradation, and high toxicity to human cells. This review will discuss the challenges associated with making LL-37 into a viable antibiotic treatment option, with a focus on antimicrobial resistance and cross-resistance as well as adaptive responses to sub-inhibitory concentrations of the peptide. The possible methods to overcome these challenges, including immobilization techniques, LL-37 delivery systems, the development of LL-37 derivatives, and synergistic combinations will also be considered. Herein, we describe how combination therapy and structural modifications to the sequence, helicity, hydrophobicity, charge, and configuration of LL-37 could optimize the antimicrobial and anti-biofilm activities of LL-37 for future clinical use.

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Smith, Margaretha E., Marit Stockfelt, Sara Tengvall, Peter Bergman, Anders Lindén, and Ingemar Qvarfordt. "Endotoxin Exposure Increases LL-37 - but Not Calprotectin - in Healthy Human Airways." Journal of Innate Immunity 9, no. 5 (2017): 475–82. http://dx.doi.org/10.1159/000475525.

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Rationale: The antimicrobial peptides (AMPs) LL-37 and calprotectin are important players in the innate immunity of human airways. In patients with diseases characterized by bacterial colonization, the airway concentrations of these AMPs are increased. Less is known about their presence and release patterns in healthy humans. Our aim was to determine whether LL-37 and calprotectin are released after the activation of the innate immune response in the peripheral airways. Methods: Healthy volunteers underwent exposure to endotoxin and vehicle in contralateral segment bronchi. After 12 or 24 h, samples of bronchoalveolar lavage fluid (BALf) were collected bilaterally from exposed segments. Cell and AMP concentrations were assessed, as were the pro-form and active form of LL-37. Results: Both LL-37 and calprotectin were detected in cell-free BALf from both endotoxin- and vehicle-exposed segments. The concentrations of precursor and active LL-37 and neutrophils were significantly higher in endotoxin-exposed segments after 12 and 24 h, and the concentrations of LL-37 and neutrophils correlated positively. The concentrations of calprotectin were not markedly affected by exposure to endotoxin. Conclusions: Local endotoxin exposure elicits the release and activation of LL-37 but not calprotectin in healthy human peripheral airways, suggesting an inducible involvement of LL-37 in the local innate immune response.

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Meguro, Shu, Masuomi Tomita, Takeshi Katsuki, Kiyoe Kato, Henpiru Oh, Akira Ainai, Ryo Ito, Toshihide Kawai, Hiroshi Itoh, and Hideki Hasegawa. "Plasma Antimicrobial Peptide LL-37 Level Is Inversely Associated with HDL Cholesterol Level in Patients with Type 2 Diabetes Mellitus." International Journal of Endocrinology 2014 (2014): 1–6. http://dx.doi.org/10.1155/2014/703696.

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Introduction. Relation between atherosclerosis and innate immunity has attracted attention. As the antimicrobial peptide, LL-37, could have an important role in atherosclerosis, we supposed that there could be a meaningful association of plasma LL-37 level with risk factors for cardiovascular disease in subjects with type 2 diabetes mellitus.Materials and Methods. We evaluated plasma LL-37 level and other clinical markers in Japanese subjects with type 2 diabetes mellitus (n=133, 115 men and 18 women; age64.7±11.5years; HbA1c8.1±1.6%). Plasma level of LL-37 was measured by ELISA.Results. Mean plasma LL-37 level was71.2±22.3 ng/mL. Plasma LL-37 level showed significant correlations with HDL cholesterol (r=−0.450,P<0.01), triglyceride (r=0.445,P<0.01), and high sensitive C-reactive protein (r=0.316,P<0.01) but no significant correlation with age, body mass index, HbA1c, estimated glomerular filtration rate, 25-hydroxyvitamin D, or vitamin D binding protein. Multiple linear regression analysis showed significant correlations of plasma LL-37 level with HDL cholesterol (β=−0.411,P<0.01) and high sensitive C-reactive protein (β=0.193,P<0.05).Conclusion. Plasma LL-37 level was positively correlated with inflammatory markers and negatively correlated with HDL cholesterol in patients with type 2 diabetes mellitus.

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Ishvaanjil, Bayartbat, Yu-Jin Jung, Uyangaa Temuujin, Soon-Youl Lee, and Kwon-Kyoo Kang. "HETEROLOGOUS EXPRESSION OF ANTIMICROBIAL PEPTIDE LL-37 IN CHINESE CABBAGE WITH ENHANCED RESISTANCE TO PATHOGENS." Mongolian Journal of Agricultural Sciences 13, no. 2 (June 22, 2015): 124–30. http://dx.doi.org/10.5564/mjas.v13i2.531.

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The human antimicrobial peptide, LL-37 gene was overexpressed in Chinese cabbage ‘Osome’ (Brassica rapa) by Agrobacterium tumefaciens-mediated transformation. In order to increase the expression of the antimicrobial peptide, we used RolA intron sequence in front of the LL-37peptide gene. We confirmed the expression of LL-37 in cabbage by RT-PCR and Western Blot analysis. Four transgenic T1 plants were confirmed that LL-37 was expressed. Cabbages expressing the humanLL-37 gene were challenged by various plant pathogen. Transgenic cabbage plants overproducing human LL-37 are expected to possess a durable and wide-spectrum resistance against various pathogens.Mongolian Journal of Agricultural Sciences Vol.13(2) 2014: 124-130

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Yang, De, Qian Chen, Albert P. Schmidt, G. Mark Anderson, Ji Ming Wang, Joseph Wooters, Joost J. Oppenheim, and Oleg Chertov. "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." Journal of Experimental Medicine 192, no. 7 (October 2, 2000): 1069–74. http://dx.doi.org/10.1084/jem.192.7.1069.

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We have previously shown that antimicrobial peptides like defensins have the capacity to mobilize leukocytes in host defense. LL-37 is the cleaved antimicrobial 37-residue, COOH-terminal peptide of hCAP18 (human cationic antimicrobial protein with a molecular size of 18 kD), the only identified member in humans of a family of proteins called cathelicidins. LL-37/hCAP18 is produced by neutrophils and various epithelial cells. Here we report that LL-37 is chemotactic for, and can induce Ca2+ mobilization in, human monocytes and formyl peptide receptor–like 1 (FPRL1)-transfected human embryonic kidney 293 cells. LL-37–induced Ca2+ mobilization in monocytes can also be cross-desensitized by an FPRL1-specific agonist. Furthermore, LL-37 is also chemotactic for human neutrophils and T lymphocytes that are known to express FPRL1. Our results suggest that, in addition to its microbicidal activity, LL-37 may contribute to innate and adaptive immunity by recruiting neutrophils, monocytes, and T cells to sites of microbial invasion by interacting with FPRL1.

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Zeth, Kornelius, and Enea Sancho-Vaello. "Structural Plasticity of LL-37 Indicates Elaborate Functional Adaptation Mechanisms to Bacterial Target Structures." International Journal of Molecular Sciences 22, no. 10 (May 14, 2021): 5200. http://dx.doi.org/10.3390/ijms22105200.

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The human cathelicidin LL-37 is a multifunctional peptide of the human innate immune system. Among the various functions of LL-37, its antimicrobial activity is important in controlling the microorganisms of the human body. The target molecules of LL-37 in bacteria include membrane lipids, lipopolysaccharides (LPS), lipoteichoic acid (LTA), proteins, DNA and RNA. In this mini-review, we summarize the entity of LL-37 structural data determined over the last 15 years and specifically discuss features implicated in the interactions with lipid-like molecules. For this purpose, we discuss partial and full-length structures of LL-37 determined in the presence of membrane-mimicking detergents. This constantly growing structural database is now composed of monomers, dimers, tetramers, and fiber-like structures. The diversity of these structures underlines an unexpected plasticity and highlights the conformational and oligomeric adaptability of LL-37 necessary to target different molecular scaffolds. The recent co-crystal structures of LL-37 in complex with detergents are particularly useful to understand how these molecules mimic lipids and LPS to induce oligomerization and fibrillation. Defined detergent binding sites provide deep insights into a new class of peptide scaffolds, widening our view on the fascinating world of the LL-37 structural factotum. Together, the new structures in their evolutionary context allow for the assignment of functionally conserved residues in oligomerization and target interactions. Conserved phenylalanine and arginine residues primarily mediate those interactions with lipids and LPS. The interactions with macromolecules such as proteins or DNA remain largely unexplored and open a field for future studies aimed at structures of LL-37 complexes. These complexes will then allow for the structure-based rational design of LL-37-derived peptides with improved antibiotic properties.

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Turner, Jeffrey, Yoon Cho, Nhu-Nguyen Dinh, Alan J. Waring, and Robert I. Lehrer. "Activities of LL-37, a Cathelin-Associated Antimicrobial Peptide of Human Neutrophils." Antimicrobial Agents and Chemotherapy 42, no. 9 (September 1, 1998): 2206–14. http://dx.doi.org/10.1128/aac.42.9.2206.

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ABSTRACT Human neutrophils contain two structurally distinct types of antimicrobial peptides, β-sheet defensins (HNP-1 to HNP-4) and the α-helical peptide LL-37. We used radial diffusion assays and an improved National Committee for Clinical Laboratory Standards-type broth microdilution assay to compare the antimicrobial properties of LL-37, HNP-1, and protegrin (PG-1). Although generally less potent than PG-1, LL-37 showed considerable activity (MIC, <10 μg/ml) againstPseudomonas aeruginosa, Salmonella typhimurium,Escherichia coli, Listeria monocytogenes,Staphylococcus epidermidis, Staphylococcus aureus, and vancomycin-resistant enterococci, even in media that contained 100 mM NaCl. Certain organisms (methicillin-resistantS. aureus, Proteus mirabilis, and Candida albicans) were resistant to LL-37 in media that contained 100 mM NaCl but were susceptible in low-salt media. Burkholderia cepacia was resistant to LL-37, PG-1, and HNP-1 in low- or high-salt media. LL-37 caused outer and inner membrane permeabilization of E. coli ML-35p. Chromogenic Limulus assays revealed that LL-37 bound to E. coli O111:B4 lipopolysaccharide (LPS) with a high affinity and that this binding showed positive cooperativity (Hill coefficient = 2.02). Circular dichroism spectrometry disclosed that LL-37 underwent conformational change in the presence of lipid A, transitioning from a random coil to an α-helical structure. The broad-spectrum antimicrobial properties of LL-37, its presence in neutrophils, and its inducibility in keratinocytes all suggest that this peptide and its precursor (hCAP-18) may protect skin and other tissues from bacterial intrusions and LPS-induced toxicity. The potent activity of LL-37 againstP. aeruginosa, including mucoid and antibiotic-resistant strains, suggests that it or related molecules might have utility as topical bronchopulmonary microbicides in cystic fibrosis.

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Hase, Koji, Lars Eckmann, John D. Leopard, Nissi Varki, and Martin F. Kagnoff. "Cell Differentiation Is a Key Determinant of Cathelicidin LL-37/Human Cationic Antimicrobial Protein 18 Expression by Human Colon Epithelium." Infection and Immunity 70, no. 2 (February 2002): 953–063. http://dx.doi.org/10.1128/iai.70.2.953-963.2002.

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ABSTRACT Antimicrobial peptides are highly conserved evolutionarily and are thought to play an important role in innate immunity at intestinal mucosal surfaces. To better understand the role of the antimicrobial peptide human cathelicidin LL-37/human cationic antimicrobial protein 18 (hCAP18) in intestinal mucosal defense, we characterized the regulated expression and production of this peptide by human intestinal epithelium. LL-37/hCAP18 is shown to be expressed within epithelial cells located at the surface and upper crypts of normal human colon. Little or no expression was seen within the deeper colon crypts or within epithelial cells of the small intestine. Paralleling its expression in more differentiated epithelial cells in vivo, LL-37/hCAP18 mRNA and protein expression was upregulated in spontaneously differentiating Caco-2 human colon epithelial cells and in HCA-7 human colon epithelial cells treated with the cell differentiation-inducing agent sodium butyrate. LL-37/hCAP18 expression by colon epithelium does not require commensal bacteria, since LL-37/hCAP18 is produced with a similar expression pattern by epithelial cells in human colon xenografts that lack a luminal microflora. LL-37/hCAP18 mRNA was not upregulated in response to tumor necrosis factor alpha, interleukin 1α (IL-1α), gamma interferon, lipopolysaccharide, or IL-6, nor did the expression patterns and levels of LL-37/hCAP18 in the epithelium of the normal and inflamed colon differ. On the other hand, infection of HCA-7 cells with Salmonella enterica serovar Dublin or enteroinvasive Escherichia coli modestly upregulated LL-37/hCAP18 mRNA expression. We conclude that differentiated human colon epithelium expresses LL-37/hCAP18 as part of its repertoire of innate defense molecules and that the distribution and regulated expression of LL-37/hCAP18 in the colon differs markedly from that of other enteric antimicrobial peptides, such as defensins.

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Perez-Perez, David A., Teresa de J. Villanueva-Ramirez, Adriana E. Hernandez-Pedraza, Nestor G. Casillas-Vega, Patricia Gonzalez-Barranco, and Xristo Zarate. "The Small Metal-Binding Protein SmbP Simplifies the Recombinant Expression and Purification of the Antimicrobial Peptide LL-37." Antibiotics 10, no. 10 (October 19, 2021): 1271. http://dx.doi.org/10.3390/antibiotics10101271.

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(1) Background: The cathelicidin peptide LL-37 is a prominent molecule with many biological activities, including antimicrobial. Due to its importance, here, we describe the production of LL-37 tagged with SmbP, a relatively new carrier protein that improves the production of recombinant proteins and peptides in Escherichia coli. We present an alternative method for the rapid expression, purification, and antimicrobial evaluation of LL-37, that involves only one purification step. (2) Methods: A DNA construct of SmbP_LL-37 was transformed into E. coli BL21(DE3); after overnight expression, the protein was purified directly from the cell lysate using immobilized metal-affinity chromatography. SmbP_LL-37 was treated with Enterokinase to obtain the free LL-37 peptide. The antimicrobial activity of both SmbP_LL-37 and free LL-37 was determined using the colony forming unit assay method. (3) Results: SmbP_LL-37 was observed in the soluble fraction of the cell lysate; after purification with IMAC, protein gel electrophoresis, and analysis by ImageJ, it showed 90% purity. A total of 3.6 mg of SmbP_LL-37 was produced from one liter of cell culture. SmbP_LL-37 and free LL-37 both showed inhibition activity against Staphylococcus aureus and Escherichia coli. (4) Conclusions: The SmbP fusion protein is a valuable tool for producing biologically-active LL-37 peptide. The production method described here should be of interest for the expression and purification of additional cationic peptides, since it cuts the purification time considerably prior to determination of antimicrobial activity.

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Nagaoka, Isao, Hiroshi Tamura, and Johannes Reich. "Therapeutic Potential of Cathelicidin Peptide LL-37, an Antimicrobial Agent, in a Murine Sepsis Model." International Journal of Molecular Sciences 21, no. 17 (August 19, 2020): 5973. http://dx.doi.org/10.3390/ijms21175973.

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Among the mechanisms put-up by the host to defend against invading microorganisms, antimicrobial peptides represent the first line. In different species of mammals, the cathelicidin family of antimicrobial peptides AMPs has been identified, and in humans, LL-37 is the only type of cathelicidin identified. LL-37 has many different biological activities, such as regulation of responses to inflammation, besides its lipopolysaccharide (LPS)-neutralizing and antimicrobial and activities. Recently, employing a murine septic model that involves cecal ligation and puncture (CLP), we examined the effect of LL-37. The results indicated that LL-37 exhibits multiple protective actions on septic mice; firstly, the survival of CLP mice was found to be improved by LL-37 by the suppression of the macrophage pyroptosis that induces the release of pro-inflammatory cytokines (such as IL-1β) and augments inflammatory reactions in sepsis; secondly, the release of neutrophil extracellular traps (NETs), which have potent bactericidal activity, is enhanced by LL-37, and protects mice from CLP-induced sepsis; thirdly, LL-37 stimulates neutrophils to release antimicrobial microvesicles (ectosomes), which improve the pathological condition of sepsis. These findings indicate that LL-37 protects CLP septic mice through at least three mechanisms, i.e., the suppression of pro-inflammatory macrophage pyroptosis and the release of antimicrobial NETs (induction of NETosis) and ectosomes from neutrophils. Thus, LL-37 can be a potential therapeutic candidate for sepsis due to its multiple properties, including the modulation of cell death (pyroptosis and NETosis) and the release of antimicrobial NETs and ectosomes as well as its own bactericidal and LPS-neutralizing activities.

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Nielsen, Karen L., Pia Dynesen, Preben Larsen, Lotte Jakobsen, Paal S. Andersen, and Niels Frimodt-Møller. "Role of Urinary Cathelicidin LL-37 and Human β-Defensin 1 in Uncomplicated Escherichia coli Urinary Tract Infections." Infection and Immunity 82, no. 4 (January 22, 2014): 1572–78. http://dx.doi.org/10.1128/iai.01393-13.

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ABSTRACTCathelicidin (LL-37) and human β-defensin 1 (hBD-1) are important components of the innate defense in the urinary tract. The aim of this study was to characterize whether these peptides are important for developing uncomplicatedEscherichia coliurinary tract infections (UTIs). This was investigated by comparing urinary peptide levels of UTI patients during and after infection to those of controls, as well as characterizing the fecal flora of participants with respect to susceptibility to LL-37 andin vivovirulence. Forty-seven UTI patients and 50 controls who had never had a UTI were included. Participants were otherwise healthy, premenopausal, adult women. LL-37 MIC levels were compared for fecalE. coliclones from patients and controls and were also compared based on phylotypes (A, B1, B2, and D).In vivovirulence was investigated in the murine UTI model by use of selected fecal isolates from patients and controls. On average, UTI patients had significantly more LL-37 in urine during infection than postinfection, and patient LL-37 levels postinfection were significantly lower than those of controls. hBD-1 showed similar urine levels for UTI patients and controls. FecalE. coliisolates from controls had higher LL-37 susceptibility than fecal and UTIE. coliisolates from UTI patients.In vivostudies showed a high level of virulence of fecalE. coliisolates from both patients and controls and showed no difference in virulence correlated with the LL-37 MIC level. The results indicate that the concentration of LL-37 in the urinary tract and low susceptibility to LL-37 may increase the likelihood of UTI in a complex interplay between host and pathogen attributes.

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Chinipardaz, Zahra, Jessica M. Zhong, and Shuying Yang. "Regulation of LL-37 in Bone and Periodontium Regeneration." Life 12, no. 10 (September 30, 2022): 1533. http://dx.doi.org/10.3390/life12101533.

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The goal of regenerative therapy is to restore the structure and function of the lost tissues in the fields of medicine and dentistry. However, there are some challenges in regeneration therapy such as the delivery of oxygen and nutrition, and the risk of infection in conditions such as periodontitis, osteomyelitis, etc. Leucine leucine-37 (LL-37) is a 37-residue, amphipathic, and helical peptide found only in humans and is expressed throughout the body. It has been shown to induce neovascularization and vascular endothelial growth factor (VEGF) expression. LL-37 also stimulates the migration and differentiation of mesenchymal stem cells (MSCs). Recent studies have shown that LL-37 plays an important role in the innate defense system through the elimination of pathogenic microbes and the modulation of the host immune response. LL-37 also manifests other functions such as promoting wound healing, angiogenesis, cell differentiation, and modulating apoptosis. This review summarizes the current studies on the structure, expression, and function of LL-37 and highlights the contributions of LL-37 to oral cavity, periodontium, and bone regeneration.

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Méndez-Samperio, Patricia, Elena Miranda, and Artemisa Trejo. "Expression and Secretion of Cathelicidin LL-37 in Human Epithelial Cells after Infection by Mycobacterium bovis Bacillus Calmette-Guérin." Clinical and Vaccine Immunology 15, no. 9 (June 25, 2008): 1450–55. http://dx.doi.org/10.1128/cvi.00178-08.

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ABSTRACT The antimicrobial cathelicidin LL-37 is considered to play an important role in the innate immune response to tuberculosis infection. However, little is known about the induction and secretion of this antimicrobial peptide in A549 epithelial cells after infection with Mycobacterium bovis bacillus Calmette-Guérin (BCG), the world's most widely used tuberculosis vaccine. In this study, we investigated the effect of M. bovis BCG on LL-37 mRNA levels in A549 cells by real-time PCR and on protein levels by Western blotting. Treatment of cells with M. bovis BCG upregulates LL-37 mRNA expression in a dose- and time-dependent manner. The quantitative analysis of LL-37 gene expression correlated with our Western blotting results. Moreover, our results demonstrated that treatment of cells with the transcriptional inhibitor actinomycin D effectively inhibited in a concentration-dependent manner the ability of M. bovis BCG to induce LL-37 mRNA expression. Finally, inhibition of the MEK1/2 and p38 mitogen-activated protein kinase (MAPK) signaling pathways reduced M. bovis BCG-mediated LL-37 mRNA expression, a reduction that correlated with the observed high level of downregulation of LL-37 protein induction. Thus, these results indicate that the MEK1/2 and p38 MAPK signaling pathways play a critical role in the regulation of inducible LL-37 gene expression in A549 cells infected with M. bovis BCG.

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Noore, Jabeen, Adly Noore, and Bingyun Li. "Cationic Antimicrobial Peptide LL-37 Is Effective against both Extra- and Intracellular Staphylococcus aureus." Antimicrobial Agents and Chemotherapy 57, no. 3 (December 28, 2012): 1283–90. http://dx.doi.org/10.1128/aac.01650-12.

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ABSTRACTThe increasing resistance of bacteria to conventional antibiotics and the challenges posed by intracellular bacteria, which may be responsible for chronic and recurrent infections, have driven the need for advanced antimicrobial drugs for effective elimination of both extra- and intracellular pathogens. The purpose of this study was to determine the killing efficacy of cationic antimicrobial peptide LL-37 compared to conventional antibiotics against extra- and intracellularStaphylococcus aureus. Bacterial killing assays and an infection model of osteoblasts andS. aureuswere studied to determine the bacterial killing efficacy of LL-37 and conventional antibiotics against extra- and intracellularS. aureus. We found that LL-37 was effective in killing extracellularS. aureusat nanomolar concentrations, while lactoferricin B was effective at micromolar concentrations and doxycycline and cefazolin at millimolar concentrations. LL-37 was surprisingly more effective in killing the clinical strain than in killing an ATCC strain ofS. aureus. Moreover, LL-37 was superior to conventional antibiotics in eliminating intracellularS. aureus. The kinetic studies further revealed that LL-37 was fast in eliminating both extra- and intracellularS. aureus. Therefore, LL-37 was shown to be very potent and prompt in eliminating both extra- and intracellularS. aureusand was more effective in killing extra- and intracellularS. aureusthan commonly used conventional antibiotics. LL-37 could potentially be used to treat chronic and recurrent infections due to its effectiveness in eliminating not only extracellular but also intracellular pathogens.

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Jang, Yong-Suk, Sae-Hae Kim, Ha-Yan Lee, Hojun Lee, Ju Kim, Dae-Hyuk Kim, and Kyung-Yeol Lee. "The cathelicidin LL-37 exerts its mucosal adjuvant activity via enhancing germinal center formation and dendritic cell maturation (P3234)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 124.28. http://dx.doi.org/10.4049/jimmunol.190.supp.124.28.

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Abstract Oral mucosal vaccine confers feasibility and efficacy in vaccination. However, it imposes restrictions such as difficulty in antigen delivery and poor immunogenic environment. Consequently, many studies have been concentrated to develop effective mucosal adjuvants. We determined mucosal adjuvant activity of cathelicidin LL-37 based on the previous report of its activity in parenteral vaccination, although it has not been studied in mucosal system. In oral mucosal vaccination using EGFP protein, LL-37-conjugated antigen effectively evoked the antigen-specific systemic and mucosal immunities. Notably, when the LL-37 was applied to pathogenic antigen, an EDIII of dengue virus, antibody responses with high neutralization activity was induced. Further studies on chemokine profiling induced by LL-37 in Peyer’s patch lymphocytes were well accordance with the increase in the number of germinal centers in Peyer’s patch and mesenteric lymph node by chemotactic effect of LL-37. In addition, oral priming with LL-37-conjugated antigen induced Th1- and Th17-skewed immune responses through CD11c+ CD70+ cell activation in Peyer’s patch. More interestingly, we found the expression of formyl peptide receptor-2, one of the receptors for LL-37, in subepithelial dome of Peyer’s patch and M cells. Collectively, we conclude that LL-37 can play a role as mucosal adjuvant through enhanced antigen delivery, dendritic cell maturation, and chemotactic effect by FPR-2 on M cells and subepithelial dome.

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Bodahl, Sara, Samuel Cerps, Lena Uller, and Bengt-Olof Nilsson. "LL-37 and Double-Stranded RNA Synergistically Upregulate Bronchial Epithelial TLR3 Involving Enhanced Import of Double-Stranded RNA and Downstream TLR3 Signaling." Biomedicines 10, no. 2 (February 19, 2022): 492. http://dx.doi.org/10.3390/biomedicines10020492.

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The human host defense peptide LL-37 influences double-stranded RNA signaling, but this process is not well understood. Here, we investigate synergistic actions of LL-37 and synthetic double-stranded RNA (poly I:C) on toll-like receptor 3 (TLR3) expression and signaling, and examine underlying mechanisms. In bronchial epithelial BEAS-2B cells, LL-37 potentiated poly I:C-induced TLR3 mRNA and protein expression demonstrated by qPCR and Western blot, respectively. Interestingly, these effects were associated with increased uptake of rhodamine-tagged poly I:C visualized by immunocytochemistry. The LL-37/poly I:C-induced upregulation of TLR3 mRNA expression was prevented by the endosomal acidification inhibitor chloroquine, indicating involvement of downstream TLR3 signaling. The glucocorticoid dexamethasone reduced LL-37/poly I:C-induced TLR3 expression on both mRNA and protein levels, and this effect was associated with increased IκBα protein expression, suggesting that dexamethasone acts via attenuation of NF-κB activity. We conclude that LL-37 potentiates poly I:C-induced upregulation of TLR3 through a mechanism that may involve enhanced import of poly I:C and that LL-37/poly I:C-induced TLR3 expression is associated with downstream TLR3 signaling and sensitive to inhibition of NF-κB activity.

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Sol, Asaf, Ofir Ginesin, Stella Chaushu, Laila Karra, Shunit Coppenhagen-Glazer, Isaac Ginsburg, and Gilad Bachrach. "LL-37 Opsonizes and Inhibits Biofilm Formation of Aggregatibacter actinomycetemcomitans at Subbactericidal Concentrations." Infection and Immunity 81, no. 10 (July 8, 2013): 3577–85. http://dx.doi.org/10.1128/iai.01288-12.

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ABSTRACTHost defense peptides are immediate responders of the innate immunity that express antimicrobial, immunoregulatory, and wound-healing activities. Neutrophils are a major source for oral host defense peptides, and phagocytosis by neutrophils is a major mechanism for bacterial clearance in the gingival tissue. Dysfunction of or reduction in the numbers of neutrophils or deficiency in the LL-37 host defense peptide was each previously linked with proliferation of oralAggregatibacter actinomycetemcomitanswhich resulted in an aggressive periodontal disease. Surprisingly,A. actinomycetemcomitansshows resistance to high concentrations of LL-37. In this study, we demonstrated that submicrocidal concentrations of LL-37 inhibit biofilm formation byA. actinomycetemcomitansand act as opsonins and agglutinins that greatly enhance its clearance by neutrophils and macrophages. Improved uptake ofA. actinomycetemcomitansby neutrophils was mediated by their opsonization with LL-37. Enhanced phagocytosis and killing ofA. actinomycetemcomitansby murine macrophage-like RAW 264.7 cells were dependent on their preagglutination by LL-37. AlthoughA. actinomycetemcomitansis resistant to the bactericidal effect of LL-37, our results offer a rationale for the epidemiological association between LL-37 deficiency and the expansion of oralA. actinomycetemcomitansand indicate a possible therapeutic use of cationic peptides for host defense.

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Chen, Xi, Xianqiong Zou, Guangying Qi, Ying Tang, Yong Guo, Jia Si, and Lihua Liang. "Roles and Mechanisms of Human Cathelicidin LL-37 in Cancer." Cellular Physiology and Biochemistry 47, no. 3 (2018): 1060–73. http://dx.doi.org/10.1159/000490183.

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LL-37, the C-terminal peptide of human cathelicidin antimicrobial peptide (CAMP, hCAP18), reportedly increases resistance to microbial invasion and exerts important physiological functions in chemotaxis, promotion of wound closure, and angiogenesis. Accumulating evidence indicates that LL-37 also plays a significant role in human cancer. LL-37 induces tumorigenic effects in cancers of the ovary, lung, breast, prostate, pancreas, as well as in malignant melanoma and skin squamous cell carcinoma. In contrast, LL-37 displays an anti-cancer effect in colon cancer, gastric cancer, hematologic malignancy and oral squamous cell carcinoma. Mechanistically, LL-37-induced activation of membrane receptors and subsequent signaling pathways lead to alteration of cellular functions. Different membrane receptors on various cancer cells appear to be responsible for the tissue-specific effects of LL-37. Meanwhile, the findings that vitamin D-dependent induction of cathelicidin in human macrophages activates the anti-cancer activity of tumor-associated macrophages (TAMs) and enhances antibody-dependent cellular cytotoxicity (ADCC) support critical roles of vitamin D-dependent induction of cathelicidin in cancer progression. This review describes novel advances involving the roles and mechanisms of human cathelicidin LL-37 in cancer.

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Sánchez-Peña, Francisco Javier, María de los Ángeles Romero-Tlalolini, Honorio Torres-Aguilar, Diego Sait Cruz-Hernández, Rafael Baltiérrez-Hoyos, Saraí Remedios Sánchez-Aparicio, Alba Soledad Aquino-Domínguez, and Sergio Roberto Aguilar-Ruiz. "LL-37 Triggers Antimicrobial Activity in Human Platelets." International Journal of Molecular Sciences 24, no. 3 (February 1, 2023): 2816. http://dx.doi.org/10.3390/ijms24032816.

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Platelets play a crucial role in hemostasis and the immune response, mainly by recognizing signals associated with vascular damage. However, it has recently been discovered that the antimicrobial peptide LL-37 activates platelets in functions related to thrombus formation and inflammation. Therefore, this work aims to evaluate the effect of LL-37 on the activation of antimicrobial functions of human platelets. Our results show that platelets treated with LL-37 increase the surface expression of receptors (Toll-like receptors (TLRs) 2 and -4, CD32, CD206, Dectin-1, CD35, LOX-1, CD41, CD62P, and αIIbβ3 integrins) for the recognition of microorganisms, and molecules related to antigen presentation to T lymphocytes (CD80, CD86, and HLA-ABC) secrete the antimicrobial molecules: bactericidal/permeability-increasing protein (BPI), azurocidin, human neutrophil peptide (HNP) -1, and myeloperoxidase. They also translate azurocidin, and have enhanced binding to Escherichia coli, Staphylococcus aureus, and Candida albicans. Furthermore, the supernatant of LL-37-treated platelets can inhibit E. coli growth, or platelets can employ their LL-37 to inhibit microbial growth. In conclusion, these findings demonstrate that LL-37 participates in the antimicrobial function of human platelets.

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YALÇINKAYA, Mustafa, and Şahru YÜKSEL. "Investigation of LL-37-mediated siRNA transfection." TURKISH JOURNAL OF BIOLOGY 37 (2013): 426–32. http://dx.doi.org/10.3906/biy-1208-50.

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Burton, Matthew F., and Patrick G. Steel. "The chemistry and biology of LL-37." Natural Product Reports 26, no. 12 (2009): 1572. http://dx.doi.org/10.1039/b912533g.

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Guo, Fang-Fang, and Jing-Yuan Fang. "Antimicrobial peptide LL-37 and gastrointestinal diseases." World Chinese Journal of Digestology 22, no. 35 (2014): 5454. http://dx.doi.org/10.11569/wcjd.v22.i35.5454.

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Bouzari, Navid, Nancy Kim, and Robert S. Kirsner. "Defense of the Skin with LL-37." Journal of Investigative Dermatology 129, no. 4 (April 2009): 814. http://dx.doi.org/10.1038/jid.2009.37.

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Bandurska, Katarzyna, Agnieszka Berdowska, Renata Barczyńska-Felusiak, and Piotr Krupa. "Unique features of human cathelicidin LL-37." BioFactors 41, no. 5 (September 10, 2015): 289–300. http://dx.doi.org/10.1002/biof.1225.

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Bucki, Robert, Katarzyna Leszczyńska, Andrzej Namiot, and Wojciech Sokołowski. "Cathelicidin LL-37: A Multitask Antimicrobial Peptide." Archivum Immunologiae et Therapiae Experimentalis 58, no. 1 (January 5, 2010): 15–25. http://dx.doi.org/10.1007/s00005-009-0057-2.

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Bachrach, G., G. Chaushu, M. Zigmond, E. Yefenof, A. Stabholz, J. Shapira, J. Merrick, and S. Chaushu. "Salivary LL-37 Secretion in Individuals with Down Syndrome is Normal." Journal of Dental Research 85, no. 10 (October 2006): 933–36. http://dx.doi.org/10.1177/154405910608501012.

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Antimicrobial peptides play an important role in the innate immune response. Deficiency in salivary LL-37 antimicrobial peptide has been implicated in periodontitis in patients with morbus Kostman syndrome. Down syndrome is associated with periodontitis, diminished salivary flow, and salivary immunoglobulin deficiency. In the present study, levels of LL-37 and its hCAP18 precursor were measured in saliva samples from young individuals with Down syndrome and compared with levels in those from age-matched healthy controls. LL-37 and human cathelicidin antimicrobial protein (hCAP18) were detected in whole but not in parotid saliva. hCAP18 was more abundant than LL-37. The concentrations of salivary hCAP18 and LL-37 were found to be higher in individuals with Down syndrome than in healthy controls, but their secretion rates were similar. We concluded that, while the adaptive immunity of individuals with Down syndrome is impaired at the oral mucosa, the secretion rate of the LL-37 component of the innate immune system is normal.

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Morroni, Gianluca, Laura Di Sante, Oriana Simonetti, Lucia Brescini, Wojciech Kamysz, Elzbieta Kamysz, Marina Mingoia, et al. "Synergistic effect of antimicrobial peptide LL-37 and colistin combination against multidrug-resistant Escherichia coli isolates." Future Microbiology 16, no. 4 (March 2021): 221–27. http://dx.doi.org/10.2217/fmb-2020-0204.

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Overview: The global spread of antibiotic resistance represents a serious threat for public health. Aim: We evaluated the efficacy of the antimicrobial peptide LL-37 as antimicrobial agent against multidrug-resistant Escherichia coli. Results: LL-37 showed good activity against mcr-1 carrying, extended spectrum β-lactamase- and carbapenemase-producing E. coli (minimum inhibitory concentration, MIC, from 16 to 64 mg/l). Checkerboard assays demonstrated synergistic effect of LL-37/colistin combination against all tested strains, further confirmed by time–kill and post antibiotic effect assays. MIC and sub-MIC concentrations of LL-37 were able to reduce biofilm formation. Conclusion: Our preliminary data indicated that LL-37/colistin combination was effective against multidrug-resistant E. coli strains and suggested a new possible clinical application.

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Habes, Chahrazed, Günther Weber, and Caroline Goupille. "Sulfated Glycoaminoglycans and Proteoglycan Syndecan-4 Are Involved in Membrane Fixation of LL-37 and Its Pro-Migratory Effect in Breast Cancer Cells." Biomolecules 9, no. 9 (September 12, 2019): 481. http://dx.doi.org/10.3390/biom9090481.

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Initially characterized by its antimicrobial activities, LL-37 has also been shown to significantly contribute to tumor development. On breast cancer cell lines, LL-37 increases intracellular calcium via the TRPV2 channel and their migration via the activation of PI3K/AKT signaling. Its all-d enantiomer d-LL-37 induces similar effects, which excludes a protein-protein interaction of LL-37 in a classic ligand-receptor manner. Its net charge of +6 gave rise to the hypothesis that the peptide uses the negative charges of sulfoglycans or sialic acids to facilitate its attachment to the cell membrane and to induce its activities. Whereas several vegetal lectins, specifically attaching to sialylated or sulfated structures, blocked the activities of LL-37 on both calcium increase and cell migration, several sialidases had no effect. However, the competitive use of free sulfated glycoaminoglycans (GAGs) as chrondroitin and heparin, or treatment of the cell surface with chondroitinase and heparinase resulted in an activity loss of 50–100% for LL-37. Concordant results were obtained by blocking the synthesis of GAGs with 4-Methylumbelliferyl-β-d-xyloside, and by suppression of glycan sulfatation by sodium chlorate. Using a candidate approach by suppressing proteoglycan synthesis using RNA interference, syndecan-4 was shown to be required for the activities of LL-37 and its binding to the cell surface. This leads to the conclusion that syndecan-4, by means of sulfated GAGs, could act as a receptor for LL-37.

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Journal articles on the topic 'LL-37'

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