Synergistic actions of antibacterial neutrophil defensins and cathelicidins

Nagaoka, Isao; Hirota, Satoko; Yomogida, Shin; Ohwada, Akihiko; Hirata, Michimasa

doi:10.1007/s000110050561

Cited by 177 publications

(193 citation statements)

References 31 publications

(57 reference statements)

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“…The majority of the experiments were carried out using LL-37-U, synthetic LL-37 with a sequence identical to the biologically active form and no isotopic labels. CD spectroscopy was used to confirm that this synthetic peptide behaved as reported previously in the literature (18,19,25,26), exhibiting a random coil structure in pure water and a primarily helical signature in the presence of anions or lipids at micromolar peptide concentrations (data not shown). A second sample of LL-37, LL-37-L, was synthesized incorporating site-specific isotopic labels: 15 NVal 21 , 13 CdO-Leu 31 , and 13 C R -Ala 13 .…”

Section: Resultssupporting

confidence: 68%

Mechanism of Lipid Bilayer Disruption by the Human Antimicrobial Peptide, LL-37

2003

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LL-37 is an amphipathic, R-helical, antimicrobial peptide. 15 N chemical shift and 15 N dipolarshift spectroscopy of site-specifically labeled LL-37 in oriented lipid bilayers indicate that the amphipathic helix is oriented parallel to the surface of the bilayer. This surface orientation is maintained in both anionic and zwitterionic bilayers and at different temperatures and peptide concentrations, ruling out a barrelstave mechanism for bilayer disruption by LL-37. In contrast, electrostatic factors, the type of lipid, and the presence of cholesterol do affect the extent to which LL-37 perturbs the lipids in the bilayer as observed with 31 P NMR. The 31 P spectra also show that micelles or other small, rapidly tumbling membrane fragments are not formed in the presence of LL-37, excluding a detergent-like mechanism. LL-37 does increase the lamellar to inverted hexagonal phase transition temperature of both PE model lipid systems and Escherichia coli lipids, demonstrating that it induces positive curvature strain in these environments. These results support a toroidal pore mechanism of lipid bilayer disruption by LL-37.

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Section: Resultssupporting

confidence: 68%

Mechanism of Lipid Bilayer Disruption by the Human Antimicrobial Peptide, LL-37

2003

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“…Human CAP18 and guinea pig CAP11 peptides can exhibit the antibacterial activities against Gram-negative and Gram-positive bacteria in the extracellular milieu containing a physiological concentration of NaCl (150 mM), whereas the antibacterial activities of defensins are completely lost under these conditions (48). Moreover, we have argued in this study that CAP18 and CAP11 could bind to LPS and CD14 and neutralize the activities of LPS.…”

Section: Discussionmentioning

confidence: 64%

Cathelicidin Family of Antibacterial Peptides CAP18 and CAP11 Inhibit the Expression of TNF-α by Blocking the Binding of LPS to CD14+ Cells

Nagaoka

Hirota

Niyonsaba

et al. 2001

The Journal of Immunology

248

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Mammalian myeloid and epithelial cells express several kinds of antibacterial peptides (α-/β-defensins and cathelicidins) that contribute to the innate host defense by killing invading micro-organisms. In this study we evaluated the LPS-neutralizing activities of cathelicidin peptides human CAP18 (cationic antibacterial proteins of 18 kDa) and guinea pig CAP11 using the CD14+ murine macrophage cell line RAW264.7 and the murine endotoxin shock model. Flow cytometric analysis revealed that CAP18 and CAP11 inhibited the binding of FITC-conjugated LPS to RAW264.7 cells. Likewise, Northern and Western blot analyses indicated that CAP18 and CAP11 suppressed LPS-induced TNF-α mRNA and protein expression by RAW264.7 cells. Interestingly, CAP18 and CAP11 possessed LPS-binding activities, and they strongly suppressed the interaction of LPS with LPS binding protein that mediates the transport of LPS to CD14 to facilitate the activation of CD14+ cells by LPS. Moreover, when CAP18 and CAP11 were preincubated with RAW264.7 cells, they bound to the cell surface CD14 and inhibited the binding of FITC-LPS to the cells. Furthermore, in the murine endotoxin shock model, CAP18 or CAP11 administration inhibited the binding of LPS to CD14+ cells (peritoneal macrophages) and suppressed LPS-induced TNF-α expression by these cells. Together these observations indicate that cathelicidin peptides CAP18 and CAP11 probably exert protective actions against endotoxin shock by blocking the binding of LPS to CD14+ cells, thereby suppressing the production of cytokines by these cells via their potent binding activities for LPS and CD14.

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“…α-Defensins are relatively ineffective against most of the oral microbes tested, with the exceptions of Capnocytophaga ochracea and C. albicans. However, synergy between HNP-1 and LL-37 has been demonstrated against E. coli and Staphylococcus aureus even at physiological salt concentrations (150 mM) (Nagaoka et al, 2000). HNP-1 requires target microbes to be metabolically active (Edgerton, et al, 2000).…”

Section: Efficacy Of Antimicrobial Peptides In the Oral Cavitymentioning

confidence: 99%

“…The oral cavity also provides an environment that allows optimal effectiveness of these peptides. Activity of most of the oral antimicrobial peptides is inhibited by ions/salt at physiologic levels (Goldman et al, 1997;Nagaoka et al, 2000;Turner et al, 1998); however, in the oral environment, they function at the surface away from high salt concentrations and interfering substances in the blood. Table 2 provides data from numerous sources on the activity of these peptides against various, mainly pathogenic, oral bacteria and fungi (see table for references for this section).…”

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confidence: 99%

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Antimicrobial Peptides in the Oral Environment: Expression and Function in Health and Disease

2005

Current Issues in Molecular Biology

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The oral cavity is a unique environment in which antimicrobial peptides play a key role in maintaining health and may have future therapeutic applications. Present evidence suggests that α-defensins, β-defensins, LL-37, histatin, and other antimicrobial peptides and proteins have distinct but overlapping roles in maintaining oral health and preventing bacterial, fungal, and viral adherence and infection. The expression of the inducible hBD-2 in normal oral epithelium, in contrast to other epithelia, and the apparent differential signaling in response to commensal and pathogenic organisms, provides new insights into innate immunity in this body site. Commensal bacteria are excellent inducers of hBD-2 in oral epithelial cells, suggesting that the commensal bacterial community acts in a manner to benefit the overall innate immune readiness of oral epithelia. This may have major significance for understanding host defense in the complex oral environment. The oral environmentThe oral cavity is a unique environment. Oral mucosa is a critical protective interface between external and internal environments and must serve as a barrier to the myriad microbial species present in this warm, moist environment. The oral cavity is the only area of the body in which hard tissues break through the epithelial surface. The periodontal epithelium surrounding the tooth is specialized to form an attachment and seal around each tooth. This unique function imparts special challenges to the tissue and leads to certain vulnerabilities associated with periodontal disease, especially in view of the continual exposure to the bacterial biofilm (dental plaque) that forms on the tooth surface at the junction of the soft tissue. Thus, this anatomical region is one where there is a significant risk of bacterially induced infection and inflammation.Antimicrobial peptides are important contributors to maintaining the balance between health and disease in this complex environment. These include several salivary antimicrobial peptides, the β-defensins expressed in the epithelium, the α-defensins expressed in neutrophils, and the cathelicidin, LL-37, expressed in both epithelium and neutrophils. These peptides are part of the host innate immune response in this environment. Epithelia, polymorphonuclear leukocytes (neutrophils), and saliva all contribute to the maintaining the health of the oral cavity in overlapping but independent ways. This review will focus on the human oral cavity and include 1) the expression and function of antimicrobial peptides in the oral cavity in the context of innate immune responses, 2) regulation of β-defensins which has led to advances in our understanding of oral epithelial innate immunity, and 3) functional efficacy against oral microbes when it is known. Epithelial antimicrobial peptidesHistorically, the oral epithelium has been considered mainly as a passive covering that becomes damaged and ulcerated in disease. This view has changed dramatically and the epithelial compartment is now seen as providing both...

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Synergistic actions of antibacterial neutrophil defensins and cathelicidins

Cited by 177 publications

References 31 publications

Mechanism of Lipid Bilayer Disruption by the Human Antimicrobial Peptide, LL-37

Mechanism of Lipid Bilayer Disruption by the Human Antimicrobial Peptide, LL-37

Cathelicidin Family of Antibacterial Peptides CAP18 and CAP11 Inhibit the Expression of TNF-α by Blocking the Binding of LPS to CD14+ Cells

Antimicrobial Peptides in the Oral Environment: Expression and Function in Health and Disease

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