Salivary LL-37 Secretion in Individuals with Down Syndrome is Normal

Bachrach, Gilad; Chaushu, Gavriel; Zigmond, Maora; Yefenof, Eitan; Stabholz, Adam; Shapira, Joseph; Merrick, Joav; Chaushu, Stella

doi:10.1177/154405910608501012

Cited by 30 publications

(19 citation statements)

References 26 publications

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“…The antimicrobial capacity that was measured, therefore, was the mucin-independent antimicrobial capacity. It must be acknowledged, however, that mucins also have antimicrobial properties and contribute to the synergistic mucosal defences (often working in complex with AMPs) (Amerongen and Veerman 2002), so fresh saliva may be more appropriate. Nevertheless, the assay employed in the present study could provide a useful indication of salivary antimicrobial capacity and may be sensitive to any changes in overall salivary antimicrobial capacity, that are caused by changes in the other salivary 'defence' factors (such as AMPs for example).…”

Section: Discussionmentioning

confidence: 99%

“…In neutrophils, the a-defensins play a role in the oxygenindependent killing of phagocytosed microorganisms (De Smet and Contreras 2005). Human cathelicidin is a 37 amino acid peptide, starting with 2 leucine residues (hence the name, LL-37), that is expressed in neutrophils, epithelial cells (Bals 2000;De Smet and Contreras 2005), and salivary glands (Murakami et al 2002); it can be detected in whole but not parotid saliva (Bachrach et al 2006). LL-37 may contribute to host defence due to both antimicrobial and immunomodulatory functions.…”

Section: Introductionmentioning

confidence: 98%

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Salivary antimicrobial peptides (LL-37 and alpha-defensins HNP1–3), antimicrobial and IgA responses to prolonged exercise

2009

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There are many factors in mucosal secretions that contribute to innate immunity and the 'first line of defence' at mucosal surfaces. Few studies, however, have investigated the effects of exercise on many of these 'defence' factors. The aim of the present study was to determine the acute effects of prolonged exercise on salivary levels of selected antimicrobial peptides (AMP) that have not yet been studied in response to exercise (HNP1-3 and LL-37) in addition to immunoglobulin A (IgA). A secondary objective was to assess the effects of exercise on saliva antibacterial capacity. Twelve active men exercised on a cycle ergometer for 2.5 h at approximately 60% of maximal oxygen uptake. Unstimulated whole saliva samples were obtained before and after exercise. There was a significant decrease (P < 0.05) in salivary IgA:osmolality ratio, following exercise, but IgA concentration and secretion rate were unaltered. Salivary HNP1-3 and LL-37 concentrations (P < 0.01 and P < 0.05, respectively), concentration:osmolality ratios (P < 0.01) and secretion rates (P < 0.01) all increased following exercise. Salivary antibacterial capacity (against E. coli) did not change. The increased concentration of AMPs in saliva may confer some benefit to the 'first line of defence' and could result from synergistic compensation within the mucosal immune system and/or airway inflammation and epithelial damage. Further study is required to determine the significance of such changes on the overall 'defence' capacity of saliva and how this influences the overall risk for infection.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Salivary antimicrobial peptides (LL-37 and alpha-defensins HNP1–3), antimicrobial and IgA responses to prolonged exercise

2009

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“…Antiprotease cocktail (1 l; Sigma-Aldrich) was added where indicated. Following incubation (as indicated in the figure legends), reaction mixtures were loaded on a 15% sodium dodecyl sulfate (SDS)-acrylamide gel, and remaining LL-37 or rhCAP18 was detected using Western immunodetection as described before (4).…”

Section: Salivamentioning

confidence: 99%

Saliva Enables the Antimicrobial Activity of LL-37 in the Presence of Proteases of Porphyromonas gingivalis

et al. 2009

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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.Cationic antimicrobial peptides are components of the innate immunity that mediate a broad range of antimicrobial activity and play an important role in mucosal protection (48). In mammals, antimicrobial peptides also function as immunomodulators of the innate immune system that alter gene expression in host cells, induce or modulate chemokine and cytokine production, and elicit or inhibit proinflammatory responses (6,24,40,46). Since the recognition of their immunoregulatory functions, antimicrobial peptides are often referred to as host defense peptides. The ␣-and ␤-defensins, histatins, and LL-37 antimicrobial peptides play an important role in protection of the oral cavity (7,11,20,36). LL-37, the only human host defense peptide of the cathelicidin family, is cleaved extracellularly from its 18-kDa human cationic antimicrobial protein (hCAP18) precursor into the biologically active 37-amino-acid antimicrobial peptide.Periodontitis is a chronic inflammatory disease that leads to destruction of the attachment apparatus of the teeth. Deficiency of salivary LL-37 in patients with morbus Kostmann syndrome (36) or with Papillon-Lefevre syndrome (10) was previously correlated with severe periodontitis. Porphyromonas gingivalis is an oral anaerobe and the pathogen most associated with chronic periodontal disease (16,18,42). P. gingivalis has previously been found to be highly resistant to antimicrobial peptides (1, 33). The Arg-gingipains and Lys-gingipain cysteine proteases (cleaving after arginine and lysine, respectively) are among the major virulence factors expressed and secreted by P. gingivalis. Being positively charged, arginine and lysine are highly represented in host defense peptides, including LL-37 (which has five arginines and six lysines). Not surprisingly, P. gingivalis w...

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“…LL-37 (LLGDFFRKSKEKIGKEFKRIVQRIKDFLRNLVP RTES) was synthesized as described previously by the solid-phase method on a fully automated, programmable peptide synthesizer (2). Peptide integrity and purity (greater than 95%) were determined by analytical highperformance liquid chromatography and mass spectrometry (MS).…”

Section: Methodsmentioning

confidence: 99%

The Antibacterial Activity of LL-37 against Treponema denticola Is Dentilisin Protease Independent and Facilitated by the Major Outer Sheath Protein Virulence Factor

2012

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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 denticola is an oral anaerobic spirochete closely associated with the pathogenesis of periodontal disease. The T. denticola major 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 and T. denticola. The three T. denticola strains 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 of T. denticola to LL-37. Furthermore, dentilisin activity was found to be inhibited by human saliva. In contrast, a deficiency of the T. denticola MSP 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 protect T. denticola from LL-37. Rather, the rapid, MSPmediated 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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Salivary LL-37 Secretion in Individuals with Down Syndrome is Normal

Cited by 30 publications

References 26 publications

Salivary antimicrobial peptides (LL-37 and alpha-defensins HNP1–3), antimicrobial and IgA responses to prolonged exercise

Salivary antimicrobial peptides (LL-37 and alpha-defensins HNP1–3), antimicrobial and IgA responses to prolonged exercise

Saliva Enables the Antimicrobial Activity of LL-37 in the Presence of Proteases of Porphyromonas gingivalis

The Antibacterial Activity of LL-37 against Treponema denticola Is Dentilisin Protease Independent and Facilitated by the Major Outer Sheath Protein Virulence Factor

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