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Last updated: 13th August 2010

Literature
Differential and coordinated expression of defensins and cytokines by gingival epithelial cells and dendritic cells in response to oral bacteria.
Yin L, Chino T, Horst OV, Hacker BM, Clark EA, Dale BA, Chung WO
Department of Oral Biology, School of Dentistry, University of Washington, 1959 NE Pacific Street, Seattle, WA 98195, Box 357132, USA. leiyin@u.washington.edu
BMC Immunol. 2010 ;11 37
Abstract
BACKGROUND: Epithelial cells and dendritic cells (DCs) both initiate and contribute to innate immune responses to bacteria. However, much less is known about the coordinated regulation of innate immune responses between GECs and immune cells, particularly DCs in the oral cavity. The present study was conducted to investigate whether their responses are coordinated and are bacteria-specific in the oral cavity. RESULTS: The beta-defensin antimicrobial peptides hBD1, hBD2 and hBD3 were expressed by immature DCs as well as gingival epithelial cells (GECs). HBD1, hBD2 and hBD3 are upregulated in DCs while hBD2 and hBD3 are upregulated in GECs in response to bacterial stimulation. Responses of both cell types were bacteria-specific, as demonstrated by distinctive profiles of hBDs mRNA expression and secreted cytokines and chemokines in response to cell wall preparations of various bacteria of different pathogenicity: Fusobacterium nucleatum, Actinomyces naeslundii and Porphyromonas gingivalis. The regulation of expression of hBD2, IL-8, CXCL2/GRObeta and CCL-20/MIP3alpha by GECs was greatly enhanced by conditioned medium from bacterially activated DCs. This enhancement was primarily mediated via IL-1beta, since induction was largely attenuated by IL-1 receptor antagonist. In addition, the defensins influence DCs by eliciting differential cytokine and chemokine secretion. HBD2 significantly induced IL-6, while hBD3 induced MCP-1 to approximately the same extent as LPS, suggesting a unique role in immune responses. CONCLUSIONS: The results suggest that cytokines, chemokines and beta-defensins are involved in interaction of these two cell types, and the responses are bacteria-specific. Differential and coordinated regulation between GECs and DCs may be important in regulation of innate immune homeostasis and response to pathogens in the oral cavity.
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Beta defensin-1 gene (DEFB1) polymorphisms are not associated with atopic dermatitis in children and adolescents from northeast Brazil (Recife, Pernambuco).
Segat L, Guimares RL, Brando LA, Rocha CR, Zanin V, Trevisiol C, de Lima Filho JL, Crovella S
Laboratory of Immunopathology Keizo Asami (LIKA), Federal University of Pernambuco, Recife, Brazil. segat@burlo.trieste.it
Int. J. Dermatol. 2010 Jun;49 (6):653-7
Abstract
BACKGROUND: Atopic dermatitis (AD) is a common inflammatory skin disease resulting from the interplay between environmental, immunological and genetic factors. In our study, we investigated the role of three single nucleotide polymorphisms (SNPs) at 5´-UTR of DEFB1 gene, encoding for the human beta defensin-1, on the susceptibility to develop AD in a group of Brazilian children and adolescents. METHODS: Three SNPs, -20 G/A (rs11362), -44 C/G (rs1800972), and -52 G/A (rs1799946) at 5´-UTR of DEFB1 gene were genotyped in two groups of children and adolescents, one affected by AD (96 subjects), the other healthy (191 individuals), from northeast Brazil. RESULTS: -44 C/G frequencies were comparable between the two groups. The -20 GG genotype was more frequent in AD subjects than in healthy controls; the -52 GG, conversely, was more frequent in healthy controls than in AD. However, both these differences did not reach statistical significance. Also, association between SNPs and AD severity has been shown. The analysis of DEFB1 haplotypes did not highlight any association of the three SNPs with AD development or disease severity. CONCLUSIONS: Our results seem to exclude a role for the -44 C/G DEFB1 SNPs on the pathogenesis and severity of AD, while for the -20 C/G and -52 G/A, even if not statistically significant, we evidenced a slight trend for susceptibility (-20 GG) and protection (-52 GG) for the development of AD. However, as controversial findings have been reported in the literature, the role of DEFB1 in the development of AD and in the severity of the phenotype deserves further investigation.
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Legionella pneumophila induces human beta Defensin-3 in pulmonary cells.
Scharf S, Vardarova K, Lang F, Schmeck B, Opitz B, Flieger A, Heuner K, Hippenstiel S, Suttorp N, N´Guessan PD
Department of Internal Medicine/Infectious Diseases and Pulmonary Medicine, Charit-Universittsmedizin Berlin, Germany.
Respir. Res. 2010 ;11 93
Abstract
BACKGROUND: Legionella pneumophila is an important causative agent of severe pneumonia in humans. Human alveolar epithelium and macrophages are effective barriers for inhaled microorganisms and actively participate in the initiation of innate host defense. The beta defensin-3 (hBD-3), an antimicrobial peptide is an important component of the innate immune response of the human lung. Therefore we hypothesize that hBD-3 might be important for immune defense towards L. pneumophila. METHODS: We investigated the effects of L. pneumophila and different TLR agonists on pulmonary cells in regard to hBD-3 expression by ELISA. Furthermore, siRNA-mediated inhibition of TLRs as well as chemical inhibition of potential downstream signaling molecules was used for functional analysis. RESULTS: L. pneumophila induced release of hBD-3 in pulmonary epithelium and alveolar macrophages. A similar response was observed when epithelial cells were treated with different TLR agonists. Inhibition of TLR2, TLR5, and TLR9 expression led to a decreased hBD-3 expression. Furthermore expression of hBD-3 was mediated through a JNK dependent activation of AP-1 (c-Jun) but appeared to be independent of NF-kappaB. Additionally, we demonstrate that hBD-3 elicited a strong antimicrobial effect on L. pneumophila replication. CONCLUSIONS: Taken together, human pulmonary cells produce hBD-3 upon L. pneumophila infection via a TLR-JNK-AP-1-dependent pathway which may contribute to an efficient innate immune defense.
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[Changes in some immunological parameters of lacrimal fluid in excess scarring after antiglaucoma surgery in patients with primary open-angle glaucoma]
Vestn Oftalmol ;126 (3):25-9
Abstract
Twenty-two patients in whom the expression of the human beta-defensin-2 (HBD-2) gene and the concentrations of human neutrophil peptides (HNP 1-3) and interleukin-17 (IL-17) were determined in the conjunctiva and lacrimal fluid were followed. In patients with primary open-angle glaucoma, the baseline concentrations of HNP 1-3 and IL-17 in lacrimal fluid and the expression of the HBD-2 gene in the conjunctival epithelial cells were higher than those in healthy individuals. The appearance of signs of pathological scarring was observed when HBD-2 expression in the conjunctival epithelial cells was lower and the rate of changes in the lacrimal fluid concentrations of HNP 1-3 and IL-17 was stable.
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Insight into invertebrate defensin mechanism of action: oyster defensins inhibit peptidoglycan biosynthesis by binding to lipid II.
Schmitt P, Wilmes M, Pugniere M, Aumelas A, Bachere E, Sahl HG, Schneider T, Destoumieux-Garzon D
CNRS, Ifremer, IRD, and University of Montpellier 2 - Lagoon ecosystems laboratory (UMR 5119), France;
The Journal of biological chemistry 2010 Jul
Abstract
Three oyster defensin variants (Cg-Defh1, Cg-Defh2 and Cg-Defm) were produced as recombinant peptides and characterized in terms of activities and mechanism of action. In agreement with their spectrum of activity almost specifically directed against Gram-positive bacteria, oyster defensins were shown here to be specific inhibitors of a bacterial biosynthesis pathway rather than mere membrane active agents. Indeed, at lethal concentrations, the three defensins did not compromise Staphylococcus aureus membrane integrity but inhibited the cell-wall biosynthesis as indicated by the accumulation of the UDP-N-acetylmuramyl-pentapeptide cell wall precursor. In addition, a combination of antagonization assays, thin layer chromatography and surface plasmon resonance measurements showed that oyster defensins bind almost irreversibly to the lipid II peptidoglycan precursor, thereby inhibiting the cell-wall biosynthesis. To our knowledge, this is the first detailed analysis of the mechanism of action of antibacterial defensins produced by invertebrates. Interestingly, the three defensins, which were chosen as representative of the oyster defensin molecular diversity, bound differentially to lipid II. This correlated with their differential antibacterial activities. From our experimental data and the analysis of oyster defensin sequence diversity, we propose that oyster defensin activity results from selective forces that have (i) conserved residues involved in lipid II-binding, and (ii) diversified residues at the surface of oyster defensins that could improve electrostatic interactions with the bacterial membranes.
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Influence of alemtuzumab on the intestinal Paneth cells and microflora in macaques.
Li Q, Zhang Q, Wang C, Tang C, Zhang Y, Jiang S, Li N, Li J
Research Institute of General Surgery, Jinling Hospital, Nanjing 210002, China; School of Medicine, Nanjing University, Nanjing 210093, China.
Clinical immunology (Orlando, Fla.) 2010 Sep;136 (3):375-386
Abstract
Alemtuzumab has been recently introduced for induction therapy in organ transplantation. However, the pathogenesis and molecular mechanism of the impact of such induction therapy on bacterial infections remain to be clarified. We found the alterations of Paneth cells including abnormal Paneth cell granules and expression of lysozyme and defensin 5 in response to lymphocyte depletion by alemtuzumab. Lymphocyte depletion resulted in decreased expression of TNF-alpha, IFN-gamma, IL-10 and TGF-beta in the intestine. The diversity of gut bacteria varied significantly between different times of alemtuzumab treatment. Abnormal expression of granule peptides might result in impairment of host gut microflora. The alterations in bacterial microflora had almost reversed 56days after alemtuzumab treatment, which was consistent with our results that Paneth cells were recovered to secrete antimicrobial peptides to govern gut microflora. These findings indicated the associations between changes of Paneth cell function and gut microflora and supported the important role of Paneth cells to barrier impairment with the use of alemtuzumab in organ transplantation.
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In vitro bactericidal activity of human beta-defensin 2 against nosocomial strains.
Routsias JG, Karagounis P, Parvulesku G, Legakis NJ, Tsakris A
Department of Microbiology, School of Medicine, National and Kapodistrian University of Athens, 75 M.Asias St., 11527 Athens, Greece. jroutsias@med.uoa.gr
Peptides. 2010 Sep;31(9):1654-60.
Abstract
Human beta-defensin 2 (hBD-2) is a 41-amino acid cationic peptide of the innate immune system that serves as antimicrobial molecule. We determined the bactericidal activity of synthetic hBD-2 against nosocomial strains belonging to eight different bacterial species and exhibiting various antimicrobial resistance phenotypes. The native disulfide connectivity was found essential for the bactericidal activity of hBD-2, while sodium chloride concentration was reversely associated with its potency. hBD-2 exhibited high bactericidal activity against Acinetobacter baumannii, Pseudomonas aeruginosa, Enterococcus faecalis, Enterococcus faecium and Staphylococcus aureus clinical strains. Characteristically, A. baumannii strains that exhibited multi-drug resistant (MDR) phenotypes were susceptible to lower concentrations of hBD-2 (vLD(90)=3.25-4.5mug/ml) in comparison with non-MDR (wild-type) A. baumannii strains (vLD(90)=3.90-9.35mug/ml). Bactericidal activity of hBD-2 was less pronounced against Escherichia coli, Klebsiella pneumoniae and Proteus mirabilis strains but was significantly enhanced against strains of these species that exhibited resistance to several beta-lactam antibiotics. These observations give indications that the natural hBD-2 has a potential therapeutic role against bacterial pathogens and particularly against those exhibiting MDR phenotypes.
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Recombinant porcine beta-defensin 1 (PBD-1) expressed in the milk by transplanting transgenic mES-like derived cells into mouse mammary gland.
Huang HJ, Gao QS, Qian YG, Zhang YD, Tao BF, Xiang M, Peng J, Jiang SW, Hause B
Cell biology international 2010 Jul
Abstract
Embryonic stem (ES) derived cells have been investigated in many animal models of severe injury and degenerative disease. However, few studies have examined the ability of ES derived cells to improve functional outcome following breast damaged partly, also on the breast modification of mammalians for some costly proteins. This study investigates the feasibility of implanting mouse ES derived keratinocyte-like (mES-dK) cells stably transfected with a mammary gland special expression vector for the porcine beta-defensin 1 (PBD-1) in the developing mammary glands. Our aims were 3-fold: 1) to determine whether existing the mammary gland tissue can provide the appropriate microenvironment to augment the further differentiation of mES-dK cells into lineage-committed cells, such as mammary gland epithelial cells or luminal cells (mES-dMs); 2) to determine the ability of in vivo differentiated mES-dMs to survive, proliferate, and integrate with host tissue after grafting into mammary gland tissues of pregnant mice; and 3) to assess the ability of cell grafting to improve functional outcome following breast damaged partly, also on the breast modification of mice for PBD-1 protein secreted in the milk. Our results showed that, the ratio of the surviving cells were labeled with the myoepithelial or luminal cell markers, EMA and CALLA, was 41.7+/-15.2% and 28.4+/-9.6%, respectively. Which revealed that transplanted mES-dK cells survived, integrated in vivo and differentiated into myoepithelial or luminal cells. In addition, Western blot analysis showed that 37.5% (3/8) female transplanted mice had PBD-1 expression in their milk, and reached 0.4998, 0.5229 and 0.5195 microg/mL, respectively.
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Tertiary structure-related activity of tick defensin (persulcatusin) in the taiga tick, Ixodes persulcatus.
Isogai E, Isogai H, Okumura K, Hori H, Tsuruta H, Kurebayashi Y
Laboratory of Animal Microbiology, Department of Microbial Biotechnology, Graduate School of Agricultural Science, Tohoku University, 1-1 Amamiya, Tsutsumidori, Aoba-ku, Sendai, 981-8555, Japan, emiko@bios.tohoku.ac.jp.
Experimental & applied acarology 2010 Jul
Abstract
Defensins are small cysteine-rich cationic proteins found in both vertebrates and invertebrates constituting the front line of host innate immunity. To examine the importance of the tertiary structure of tick defensin in its antimicrobial activity, we synthesized two types of the peptides with tertiary structure or primary one on basis of the information of the sequence in the defensin originated from the taiga tick, Ixodes persulcatus. Chemically synthesized peptides were used to investigate the activity spectrum against Staphylococcus aureus, Borrelia garinii and flora-associated bacteria. Both synthetic peptides showed antimicrobial activity against S. aureus in short-time killing within 1 h, but they do not show the activity against B. garinii, Stenotrophomonas maltophila and Bacillus spp., which were frequently isolated from the midgut of I. persulcatus. The teriary structure brought more potent activity to S. aureus than primary one in short-time killing. We also examined its antimicrobial activity by evaluation of growth inhibition in the presence of the synthetic peptides. Minimum inhibitory concentration (MIC) was ranged from 1.2 to 5.0 mug/ml in tertiary peptide and from 10 to 40 mug/ml in primary peptide, when 10 strains of S. aureus were used. From the curve of cumulative inhibition rates, MIC50 (MIC which half of the strains showed) to S. aureus is about 1.2 mug/ml in the peptide with tertiary structure and about 10 mug/ml in the linear one. Corynebacterium renale is 10 times or more sensitive to tertiary peptide than primary one. In conclusion, the presence of 3 disulfide bridges, which stabilize the molecule and maintain the tertiary structure, is considered to have an effect on their antimicrobial activities against Gram-positive bacteria such as S. aureus.
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Insight into the mechanisms of adenovirus capsid disassembly from studies of defensin neutralization.
Smith JG, Silvestry M, Lindert S, Lu W, Nemerow GR, Stewart PL
Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, California, United States of America.
PLoS Pathog. 2010 ;6 (6):e1000959
Abstract
Defensins are effectors of the innate immune response with potent antibacterial activity. Their role in antiviral immunity, particularly for non-enveloped viruses, is poorly understood. We recently found that human alpha-defensins inhibit human adenovirus (HAdV) by preventing virus uncoating and release of the endosomalytic protein VI during cell entry. Consequently, AdV remains trapped in the endosomal/lysosomal pathway rather than trafficking to the nucleus. To gain insight into the mechanism of defensin-mediated neutralization, we analyzed the specificity of the AdV-defensin interaction. Sensitivity to alpha-defensin neutralization is a common feature of HAdV species A, B1, B2, C, and E, whereas species D and F are resistant. Thousands of defensin molecules bind with low micromolar affinity to a sensitive serotype, but only a low level of binding is observed to resistant serotypes. Neutralization is dependent upon a correctly folded defensin molecule, suggesting that specific molecular interactions occur with the virion. CryoEM structural studies and protein sequence analysis led to a hypothesis that neutralization determinants are located in a region spanning the fiber and penton base proteins. This model was supported by infectivity studies using virus chimeras comprised of capsid proteins from sensitive and resistant serotypes. These findings suggest a mechanism in which defensin binding to critical sites on the AdV capsid prevents vertex removal and thereby blocks subsequent steps in uncoating that are required for release of protein VI and endosomalysis during infection. In addition to informing the mechanism of defensin-mediated neutralization of a non-enveloped virus, these studies provide insight into the mechanism of AdV uncoating and suggest new strategies to disrupt this process and inhibit infection.
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