Human β‐defensin 3 binds to hemagglutinin B (rHagB), a non‐fimbrial adhesin from <i>Porphyromonas gingivalis</i>, and attenuates a pro‐inflammatory cytokine response

Pingel, Lindsey C.; Kohlgraf, Karl G.; Hansen, Christopher J.; Eastman, Christopher G.; Dietrich, Deborah E.; Burnell, Kindra K.; Srikantha, Rupasree; Xiao, Xiangjun; Bélanger, Myriam; Progulske‐Fox, Ann; Cavanaugh, Joseph E.; Guthmiller, Janet M.; Johnson, Georgia K.; Joly, Sophie; Kurago, Zoya B.; Dawson, Deborah V.; Brogden, Kim A.

doi:10.1038/icb.2008.56

Cited by 77 publications

(111 citation statements)

References 56 publications

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“…35 Unlike other β-defensins, the high positive charge (note: the net charge is +11) of hBD3 may contribute to its broad-spectrum microbial eradicating ability by binding directly to microbial pathogens. 36 The purpose of this study was to isolate a key peptide fragment from hBD3 that shows both intracellular localization activity and anti-inflammatory activity. Our results indicated that all of the hBD3 fragments that we tested in the translocation analyses (Figures 1-3) were detected both in cells and in animal skin (Figures 2 and 3).…”

Section: Discussionmentioning

confidence: 99%

Identification of a cell-penetrating peptide domain from human beta-defensin 3 and characterization of its anti-inflammatory activity

Lee¹,

Suh²,

Kim³

et al. 2015

IJN

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Human beta-defensins (hBDs) are crucial factors of intrinsic immunity that function in the immunologic response to a variety of invading enveloped viruses, bacteria, and fungi. hBDs can cause membrane depolarization and cell lysis due to their highly cationic nature. These molecules participate in antimicrobial defenses and the control of adaptive and innate immunity in every mammalian species and are produced by various cell types. The C-terminal 15-mer peptide within hBD3, designated as hBD3-3, was selected for study due to its cell- and skin-penetrating activity, which can induce anti-inflammatory activity in lipopolysaccharide-treated RAW 264.7 macrophages. hBD3-3 penetrated both the outer membrane of the cells and mouse skin within a short treatment period. Two other peptide fragments showed poorer penetration activity compared to hBD3-3. hBD3-3 inhibited the lipopolysaccharide-induced production of inducible nitric oxide synthase, nitric oxide, and secretory cytokines, such as interleukin-6 and tumor necrosis factor in a concentration-dependent manner. Moreover, hBD3-3 reduced the interstitial infiltration of polymorphonuclear leukocytes in a lung inflammation model. Further investigation also revealed that hBD3-3 downregulated nuclear factor kappa B-dependent inflammation by directly suppressing the degradation of phosphorylated-IκBα and by downregulating active nuclear factor kappa B p65. Our findings indicate that hBD3-3 may be conjugated with drugs of interest to ensure their proper translocation to sites, such as the cytoplasm or nucleus, as hBD3-3 has the ability to be used as a carrier, and suggest a potential approach to effectively treat inflammatory diseases.

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Section: Discussionmentioning

confidence: 99%

Identification of a cell-penetrating peptide domain from human beta-defensin 3 and characterization of its anti-inflammatory activity

Lee¹,

Suh²,

Kim³

et al. 2015

IJN

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“…Moreover, in addition to their antimicrobial activity, manifold immunomodulatory properties of defensins have been reported, and many of these reports describe direct effects on immune cells and cytokine expression (13-15). In some cases, the interaction of peptides with bacterial components is implicated in their immunomodulatory effects (16,17). In this context, the present study hypothesized that hBD-2 activity on E. coli could result in the generation of extracellular mediators with relevance for immunomodulation.…”

mentioning

confidence: 94%

Human β-Defensin 2 Induces Extracellular Accumulation of Adenosine in Escherichia coli

Estrela

Rohde

Gutierrez

et al. 2013

Antimicrob Agents Chemother

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Human ␤-defensins are host defense peptides performing antimicrobial as well as immunomodulatory functions. The present study investigated whether treatment of Escherichia coli with human ␤-defensin 2 could generate extracellular molecules of relevance for immune regulation. Mass spectrometry analysis of bacterial supernatants detected the accumulation of purine nucleosides triggered by ␤-defensin 2 treatment. Other cationic antimicrobial peptides tested presented variable outcomes with regard to extracellular adenosine accumulation; human ␤-defensin 2 was the most efficient at inducing this response. Structural and biochemical evidence indicated that a mechanism other than plain lysis was involved in the observed phenomenon. By use of isotope ( 13 C) labeling, extracellular adenosine was found to be derived from preexistent RNA, and a direct interaction between the peptide and bacterial nucleic acid was documented for the first time for ␤-defensin 2. Taken together, the data suggest that defensin activity on a bacterial target may alter local levels of adenosine, a well-known immunomodulator influencing inflammatory processes. Human ␤-defensins (hBD) are cationic antimicrobial peptides produced predominantly by epithelial cells (1). Notably, in the intestine, an environment populated by a dense and rich microbial community, epithelial defensins reinforce the host innate defense (2). These peptides are normally expressed at low basal levels, but hBD-2 and -3 can be upregulated by a variety of microbial and inflammatory stimuli (3, 4). In particular, altered hBD-2 expression has been reported to correlate with the development of intestinal inflammation (5, 6). On the other hand, intestinal inflammation has been associated with alterations in the microbiota-for example, with shifts in the relative abundance of Proteobacteria, such as Escherichia coli (7,8). Elucidating how the interaction between hBD and their bacterial targets impact inflammatory processes can aid our understanding of host-microbe networking in health and disease.The most-studied mechanism of action of cationic antimicrobial peptides involves membrane permeabilization with eventual cell lysis; however, other mechanisms and cellular targets have been described for many peptides, including human defensins (9-12). Moreover, in addition to their antimicrobial activity, manifold immunomodulatory properties of defensins have been reported, and many of these reports describe direct effects on immune cells and cytokine expression (13-15). In some cases, the interaction of peptides with bacterial components is implicated in their immunomodulatory effects (16,17). In this context, the present study hypothesized that hBD-2 activity on E. coli could result in the generation of extracellular mediators with relevance for immunomodulation. MATERIALS AND METHODSChemicals. Lyophilized synthetic human ␤-defensin 2, human ␤-defensin 3, and human ␣-defensin 5 were purchased from the Peptide Institute Inc., sheep myeloid antimicrobial peptide 29 (SMAP-29) from AnaSpe...

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“…In fact, DEFB123 efficiently bound LPS to the extent that mice given LPS did not die from endotoxic shock. Similarly, Pingel et al [61] showed that hBD3 attenuated a proinflammatory cytokine response to HagB (a hemagglutinin of Porphyromonas gingivalis ). HagB was shown to induce 22 cytokines and the presence of hBD3 selectively inhibited IL-6, IL-10, TNFα and GM-CSF.…”

Section: β-Defensins As Proinflammatory Suppressorsmentioning

confidence: 99%

β-Defensins: Multifunctional Modulators of Infection, Inflammation and More?

Semple

Dorin²

2012

J Innate Immun

305

241

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Defensins comprise one of the largest groups of host defence peptides, present throughout evolution, in fungi and flowering plants as well as in invertebrates and vertebrates. These cysteine-rich, cationic peptides have a common ability to kill a broad range of microorganisms including bacteria, yeast and viruses. As such, they are a strong component of the arsenal that is an organism’s innate immunity. It is becoming increasingly clear, however, that antimicrobial action is only one of the numerous roles of these multifunctional peptides. In recent years, the functions of defensins in immunomodulation have been widely investigated, and their involvement in other processes (such as fertility) is becoming evident. This review addresses recent advances in the immunomodulatory activity of β-defensins as well as the involvement of β-defensins in fertility, development, wound healing and cancer.

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Human β‐defensin 3 binds to hemagglutinin B (rHagB), a non‐fimbrial adhesin from Porphyromonas gingivalis, and attenuates a pro‐inflammatory cytokine response

Cited by 77 publications

References 56 publications

Identification of a cell-penetrating peptide domain from human beta-defensin 3 and characterization of its anti-inflammatory activity

Identification of a cell-penetrating peptide domain from human beta-defensin 3 and characterization of its anti-inflammatory activity

Human β-Defensin 2 Induces Extracellular Accumulation of Adenosine in Escherichia coli

β-Defensins: Multifunctional Modulators of Infection, Inflammation and More?

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