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

Semple, Fiona; Dorin, Julia R.

doi:10.1159/000336619

Cited by 304 publications

(254 citation statements)

References 196 publications

(129 reference statements)

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“…All other transcript types were recovered in lower levels and typically with only one or two isoforms. It is noteworthy that the ancestral activity of these two peptide types is antimicrobial (72,73)-an activity which is retained by at least some isoforms expressed in the venoms of highly toxic frontfanged snakes. Another ancestrally recruited protein type, L-amino oxidase, also has well-documented anti-microbial activity (74).…”

Section: Discussionmentioning

confidence: 99%

Squeezers and Leaf-cutters: Differential Diversification and Degeneration of the Venom System in Toxicoferan Reptiles

Fry

Undheim

Ali

et al. 2013

Molecular & Cellular Proteomics

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Although it has been established that all toxicoferan squamates share a common venomous ancestor, it has remained unclear whether the maxillary and mandibular venom glands are evolving on separate gene expression trajectories or if they remain under shared genetic control. We show that identical transcripts are simultaneously expressed not only in the mandibular and maxillary glands, but also in the enigmatic snake rictal gland. Toxin molecular frameworks recovered in this study were threefinger toxin (3FTx), CRiSP, crotamine (beta-defensin), cobra venom factor, cystatin, epididymal secretory protein, kunitz, L-amino acid oxidase, lectin, renin aspartate protease, veficolin, and vespryn. We also discovered a novel low-molecular weight disulfide bridged peptide class in pythonid snake glands. In the iguanian lizards, the most highly expressed are potentially antimicrobial in nature (crotamine (beta-defensin) and cystatin), with crotamine (beta-defensin) also the most diverse. However, a number of proteins characterized from anguimorph lizards and caenophidian snakes with hemotoxic or neurotoxic activities were recruited in the common toxicoferan ancestor and remain expressed, albeit in low levels, even in the iguanian lizards. In contrast, the henophidian snakes express 3FTx and lectin toxins as the dominant transcripts. Even in the constricting pythonid and boid snakes, where the glands are predominantly mucous-secreting, low-levels of toxin transcripts can be detected. Venom thus appears to play little role in feeding behavior of most iguanian lizards or the powerful constricting snakes, and the low levels of expression argue against a defensive role. However, clearly the incipient or secondarily atrophied venom systems of these taxa may be a source of novel compounds useful in drug design and discovery. Molecular & Cellular

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Section: Discussionmentioning

confidence: 99%

Squeezers and Leaf-cutters: Differential Diversification and Degeneration of the Venom System in Toxicoferan Reptiles

Fry

Undheim

Ali

et al. 2013

Molecular & Cellular Proteomics

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“…Furthermore, the immunomodulatory function of HDPs may include manipulation of monocyte responses and APCs at multiple points of intervention as shown for LL-37 (21,23,24). Likewise, b-defensins have been shown to bind to cell-surface receptors and modulate the immune response (25). Inspired by the discovered immunoregulatory activities of HDPs, new synthetic immune defense regulators have been designed that selectively boost parts of the immune response (26,27) and are of therapeutic potential.…”

mentioning

confidence: 99%

The Thrombin-Derived Host Defense Peptide GKY25 Inhibits Endotoxin-Induced Responses through Interactions with Lipopolysaccharide and Macrophages/Monocytes

Hansen

Kalle-Brune

Plas

et al. 2015

The Journal of Immunology

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Host defense peptides have recently gained much interest as novel anti-infectives owing to their ability to kill bacteria and simultaneously modulate host cell responses. The cationic host defense peptide GKY25 (GKYGFYTHVFRLKKWIQKVIDQFGE), derived from the C terminus of human thrombin, inhibits proinflammatory responses in vitro and in vivo, but the mode of action is unclear. In this study, we show that GKY25, apart from binding bacterial LPS, also interacts directly with monocytes and macrophages in vitro, ex vivo, and in vivo. Moreover, GKY25 inhibits TLR4- and TLR2-induced NF-κB activation in response to several microbe-derived agonists. Furthermore, GKY25 reduces LPS-induced phosphorylation of MAPKs p38α and JNK1/2/3. FACS and electron microscopy analyses showed that GKY25 interferes with TLR4/myeloid differentiation protein-2 dimerization. The results demonstrate a previously undisclosed activity of the host defense peptide GKY25, based on combined LPS and cell interactions leading to inhibition of TLR4 dimerization and subsequent reduction of NF-κB activity and proinflammatory cytokine production in monocytes and macrophages.

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“…In addition to the primarily recognized antimicrobial activities, hBD3 also functions as immune modulators linking innate and adaptive immunity (4,5). Analysis of intestinal resections obtained from infants with severe NEC revealed that low defensin mRNA and protein expression (6).…”

mentioning

confidence: 99%

Human β-defensin-3 promotes intestinal epithelial cell migration and reduces the development of necrotizing enterocolitis in a neonatal rat model

Sheng

Cai

et al. 2014

Pediatr Res

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Background:The aim of this study was to investigate the effects of human β-defensin-3 (hBD3) on intestinal wound healing and in a neonatal rat model of necrotizing enterocolitis (NEC). Methods: Enterocyte migration and proliferation were detected in vitro and in vivo. The role of chemokine receptor CCR6 and its downstream signaling pathway was assessed. Newborn Sprague-Dawley rats were randomly divided into four groups: Control+NS, Control+hBD3, NEC+NS, and NEC+hBD3. Body weight, histological score, survival time, cytokines expression, and mucosal integrity were evaluated. results: hBD3 could stimulate enterocyte migration, but not proliferation, both in cultured enterocytes and in the NEC model. Neutralizing antibody and small interfering RNA confirmed this stimulatory effect was mediated by CCR6. Furthermore, hBD3 induced Rho activation, myosin light chain 2 phosphorylation, and F-actin accumulation. The bactericidal activity of hBD3 was maintained throughout a broad pH range. Strikingly, hBD3 administration decreased the incidence of NEC, increased the survival rate, and reduced the severity of NEC. Moreover, hBD3 reduced the proinflammatory cytokines expression in ileum and serum and preserved the intestinal barrier integrity. conclusion: This study provided evidence that the antimicrobial peptide hBD3 might participate in intestinal wound healing by promoting enterocyte migration and show beneficial effects on newborn rats with NEC.

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

Cited by 304 publications

References 196 publications

Squeezers and Leaf-cutters: Differential Diversification and Degeneration of the Venom System in Toxicoferan Reptiles

Squeezers and Leaf-cutters: Differential Diversification and Degeneration of the Venom System in Toxicoferan Reptiles

The Thrombin-Derived Host Defense Peptide GKY25 Inhibits Endotoxin-Induced Responses through Interactions with Lipopolysaccharide and Macrophages/Monocytes

Human β-defensin-3 promotes intestinal epithelial cell migration and reduces the development of necrotizing enterocolitis in a neonatal rat model

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