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  • 1
    In: Nature Biotechnology, Springer Science and Business Media LLC, Vol. 25, No. 4 ( 2007-4), p. 465-472
    Materialart: Online-Ressource
    ISSN: 1087-0156 , 1546-1696
    Sprache: Englisch
    Verlag: Springer Science and Business Media LLC
    Publikationsdatum: 2007
    ZDB Id: 1494943-X
    ZDB Id: 1311932-1
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 2
    Online-Ressource
    Online-Ressource
    Oxford University Press (OUP) ; 2004
    In:  Journal of Leukocyte Biology Vol. 77, No. 4 ( 2004-11-29), p. 451-459
    In: Journal of Leukocyte Biology, Oxford University Press (OUP), Vol. 77, No. 4 ( 2004-11-29), p. 451-459
    Kurzfassung: Host defense peptides (often called cationic antimicrobial peptides) have pleiotropic immunomodulatory functions. The human host defense peptide LL-37 is up-regulated at sites of infection and has little or no antimicrobial activity in tissue-culture media but under the same conditions, demonstrates immunomodulatory effects on epithelial cells, monocytes, and dendritic cells (DC). These effects include the induction of chemokine production in a mitogen-activated protein kinase-dependent manner in epithelial cell lines and monocytes and profound alterations of DC differentiation, resulting in the capacity to enhance a T helper cell type 1 response. Although the exact mechanisms of interaction between LL-37 and these cell types have not been elucidated, there is evidence for specific (i.e., receptor-mediated) and nonspecific interactions. The relative significance of the direct antimicrobial activities and immunomodulatory properties of LL-37 and other cationic host defense peptides in host defense remains unresolved. To demonstrate that antimicrobial activity was not necessarily required for protection in vivo, model peptides were synthesized and tested for antimicrobial and immunomodulatory activities. A peptide with no antimicrobial activity was found to be protective in animal models of Staphylococcus aureus and Salmonella infection, implying that a host defense peptide can protect by exerting immunomodulatory properties.
    Materialart: Online-Ressource
    ISSN: 0741-5400 , 1938-3673
    RVK:
    Sprache: Englisch
    Verlag: Oxford University Press (OUP)
    Publikationsdatum: 2004
    ZDB Id: 2026833-6
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 3
    Online-Ressource
    Online-Ressource
    Proceedings of the National Academy of Sciences ; 2000
    In:  Proceedings of the National Academy of Sciences Vol. 97, No. 16 ( 2000-08), p. 8856-8861
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 97, No. 16 ( 2000-08), p. 8856-8861
    Kurzfassung: It is becoming clear that the cationic antimicrobial peptides are an important component of the innate defenses of all species of life. Such peptides can be constitutively expressed or induced by bacteria or their products. The best peptides have good activities vs. a broad range of bacterial strains, including antibiotic-resistant isolates. They kill very rapidly, do not easily select resistant mutants, are synergistic with conventional antibiotics, other peptides, and lysozyme, and are able to kill bacteria in animal models. It is known that bacterial infections, especially when treated with antibiotics, can lead to the release of bacterial products such as lipopolysaccharide (LPS) and lipoteichoic acid, resulting in potentially lethal sepsis. In contrast to antibiotics, the peptides actually prevent cytokine induction by bacterial products in tissue culture and human blood, and they block the onset of sepsis in mouse models of endotoxemia. Consistent with this, transcriptional gene array experiments using a macrophage cell line demonstrated that a model peptide, CEMA, blocks the expression of many genes whose transcription was induced by LPS. The peptides do this in part by blocking LPS interaction with the serum protein LBP. In addition, CEMA itself has a direct effect on macrophage gene expression. Because cationic antimicrobial peptides are induced by LPS and are able to dampen the septic response of animal cells to LPS, we propose that, in addition to their role in direct and lysozyme-assisted killing of microbes, they have a role in feedback regulation of cytokine responses. We are currently developing variant peptides as therapeutics against antibiotic-resistant infections.
    Materialart: Online-Ressource
    ISSN: 0027-8424 , 1091-6490
    RVK:
    RVK:
    Sprache: Englisch
    Verlag: Proceedings of the National Academy of Sciences
    Publikationsdatum: 2000
    ZDB Id: 209104-5
    ZDB Id: 1461794-8
    SSG: 11
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 4
    Online-Ressource
    Online-Ressource
    The American Association of Immunologists ; 2000
    In:  The Journal of Immunology Vol. 164, No. 11 ( 2000-06-01), p. 5894-5904
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 164, No. 11 ( 2000-06-01), p. 5894-5904
    Kurzfassung: Changes in macrophage phenotype induced during infection result from the recognition of bacterial products as well as the action of bacterial virulence factors. We used the unprecedented opportunity provided by gene arrays to simultaneously study the expression of hundreds of genes during Salmonella typhimurium infection of macrophages and to assess the contribution of the bacterial virulence factor, LPS, in initiating the host responses to Salmonella. We found that S. typhimurium infection caused significant changes in the expression of numerous genes encoding chemokines, cell surface receptors, signaling molecules, and transcriptional activators at 4 h postinfection of the RAW 264.7 murine macrophage cell line. Our results revealed changes in the expression of several genes that had not been previously implicated in the host responses to S. typhimurium infection, as well as changes in the expression of several genes previously shown to be regulated by S. typhimurium infection. An overlapping spectrum of genes was expressed in response to virulent S. typhimurium and purified S. typhimurium LPS, reinforcing the major role of this surface molecule in stimulating the early response of macrophages to bacterial infection. The macrophage gene expression profile was further altered by activation with IFN-γ, indicating that host cell responses depend on the activation state of the cell.
    Materialart: Online-Ressource
    ISSN: 0022-1767 , 1550-6606
    RVK:
    RVK:
    Sprache: Englisch
    Verlag: The American Association of Immunologists
    Publikationsdatum: 2000
    ZDB Id: 1475085-5
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 5
    Online-Ressource
    Online-Ressource
    The American Association of Immunologists ; 2000
    In:  The Journal of Immunology Vol. 165, No. 6 ( 2000-09-15), p. 3358-3365
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 165, No. 6 ( 2000-09-15), p. 3358-3365
    Kurzfassung: Certain cationic antimicrobial peptides block the binding of LPS to LPS-binding protein and reduce the ability of LPS to induce the production of inflammatory mediators by macrophages. To gain a more complete understanding of how LPS activates macrophages and how cationic peptides influence this process, we have used gene array technology to profile gene expression patterns in macrophages treated with LPS in the presence or the absence of the insect-derived cationic antimicrobial peptide CEMA (cecropin-melittin hybrid). We found that CEMA selectively blocked LPS-induced gene expression in the RAW 264.7 macrophage cell line. The ability of LPS to induce the expression of & gt;40 genes was strongly inhibited by CEMA, while LPS-induced expression of another 16 genes was relatively unaffected. In addition, CEMA itself induced the expression of a distinct set of 35 genes, including genes involved in cell adhesion and apoptosis. Thus, CEMA, a synthetic α-helical peptide, selectively modulates the transcriptional response of macrophages to LPS and can alter gene expression in macrophages.
    Materialart: Online-Ressource
    ISSN: 0022-1767 , 1550-6606
    RVK:
    RVK:
    Sprache: Englisch
    Verlag: The American Association of Immunologists
    Publikationsdatum: 2000
    ZDB Id: 1475085-5
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 6
    Online-Ressource
    Online-Ressource
    Begell House ; 2000
    In:  Critical Reviews™ in Immunology Vol. 20, No. 5 ( 2000), p. 24-
    In: Critical Reviews™ in Immunology, Begell House, Vol. 20, No. 5 ( 2000), p. 24-
    Materialart: Online-Ressource
    ISSN: 2162-6472
    URL: Issue
    Sprache: Englisch
    Verlag: Begell House
    Publikationsdatum: 2000
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 7
    Online-Ressource
    Online-Ressource
    American Society for Microbiology ; 2005
    In:  Infection and Immunity Vol. 73, No. 1 ( 2005-01), p. 583-591
    In: Infection and Immunity, American Society for Microbiology, Vol. 73, No. 1 ( 2005-01), p. 583-591
    Kurzfassung: LL-37 is a human cationic host defense peptide that is an essential component of innate immunity. In addition to its modest antimicrobial activity, LL-37 affects the gene expression and behavior of effector cells involved in the innate immune response, although its mode of interaction with eukaryotic cells remains unclear. The interaction of LL-37 with epithelial cells was characterized in tissue culture by using biotinylated LL-37 and confocal microscopy. It was demonstrated that LL-37 was actively taken up into A549 epithelial cells and eventually localized to the perinuclear region. Specific inhibitors were used to demonstrate that the uptake process was not mediated by actin but required elements normally involved in endocytosis and that trafficking to the perinuclear region was dependent on microtubules. By using nonlinear regression analysis, it was revealed that A549 epithelial cells have two receptors for LL-37B, with high and low affinity for LL-37, respectively. These results indicate the mode of interaction of LL-37 with epithelial cells and further our understanding of its role in modulating the innate immune response.
    Materialart: Online-Ressource
    ISSN: 0019-9567 , 1098-5522
    RVK:
    Sprache: Englisch
    Verlag: American Society for Microbiology
    Publikationsdatum: 2005
    ZDB Id: 1483247-1
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 8
    Online-Ressource
    Online-Ressource
    American Society for Microbiology ; 2005
    In:  Antimicrobial Agents and Chemotherapy Vol. 49, No. 5 ( 2005-05), p. 1727-1732
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 49, No. 5 ( 2005-05), p. 1727-1732
    Kurzfassung: Recent studies have demonstrated that in addition to their antimicrobial activity, cationic host defense peptides, like the human cathelicidin LL-37, perform many activities relating to innate immunity, including the induction or modulation of chemokine and cytokine production, alteration of gene expression in host cells, and inhibition of proinflammatory responses of host cells to bacterial components such as lipopolysaccharide (LPS) in vitro and in vivo. To investigate if these properties are shared by smaller peptides, two cathelicidin peptides derived from bovine neutrophils, the 13-mer indolicidin and Bac2A, a linear 12-amino-acid derivative of bactenecin, were compared to the 37-amino-acid peptide LL-37. Indolicidin, like LL-37, inhibited LPS-induced tumor necrosis factor alpha (TNF-α) secretion, even when added up to an hour after the addition of Escherichia coli O111:B4 LPS to the human macrophage/monocyte-like THP-1 cell line. In contrast, Bac2A demonstrated no significant antiendotoxin activity. At low concentrations, indolicidin and LL-37 acted synergistically to suppress LPS-induced production of TNF-α. Indolicidin was analogous to LL-37 in its ability to induce the production of the chemokine interleukin-8 (IL-8) in a human bronchial cell line, 16HBE14o − , but it was unable to induce production of IL-8 in THP-1 cells. In contrast, Bac2A was unable to induce IL-8 in either cell type. Conversely, Bac2A was chemotactic for THP-1 cells at concentrations between 10 and 100 μg/ml, while indolicidin and LL-37 were not chemotactic at these concentrations for THP-1 cells. This indicates that in addition to the potential for direct microbicidal activity, cationic host defense peptides may have diverse and complementary abilities to modulate the innate immune response.
    Materialart: Online-Ressource
    ISSN: 0066-4804 , 1098-6596
    RVK:
    Sprache: Englisch
    Verlag: American Society for Microbiology
    Publikationsdatum: 2005
    ZDB Id: 1496156-8
    SSG: 12
    SSG: 15,3
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 9
    Online-Ressource
    Online-Ressource
    American Society for Microbiology ; 1999
    In:  Infection and Immunity Vol. 67, No. 12 ( 1999-12), p. 6445-6453
    In: Infection and Immunity, American Society for Microbiology, Vol. 67, No. 12 ( 1999-12), p. 6445-6453
    Kurzfassung: Compounds with antiendotoxin properties have been extensively studied for their potential as therapeutic agents for sepsis attributable to gram-negative bacteria. However, with the increasing incidence of gram-positive sepsis, there is interest in identifying compounds with a broad spectrum of action against both gram-positive and gram-negative bacteria. A series of synthetic α-helical cationic peptides related to bee melittin and silk moth cecropin have previously been shown to bind lipopolysaccharide (LPS) with high affinity, inhibit LPS-induced tumor necrosis factor alpha (TNF-α) production in vitro and in vivo, and kill gram-negative bacteria. In this study, we analyzed whether these peptides were active against gram-positive bacteria; whether they could bind to lipoteichoic acid (LTA), the major proinflammatory structure on gram-positive bacteria; and whether they could block the ability of LTA to promote the release of cytokines by the RAW 264.7 murine macrophage cell line. We found that the cationic peptides demonstrated moderate growth-inhibitory activity toward gram-positive bacteria. In addition, the peptides bound LTA with high affinity. This correlated with the ability of the peptides to block LTA-induced production of TNF and interleukin-6 by RAW 264.7 cells but did not correlate with their ability to kill the bacteria. The peptides also effectively inhibited LTA-induced TNF production in a whole human blood assay. The peptides were also able to partly block the ability of heat-killed Staphylococcus aureus , as well as soluble products of live S. aureus , to stimulate cytokine production by macrophages. Our results indicate that these cationic peptides may be useful to prevent sepsis and inflammation caused by both gram-negative and gram-positive bacteria.
    Materialart: Online-Ressource
    ISSN: 0019-9567 , 1098-5522
    RVK:
    Sprache: Englisch
    Verlag: American Society for Microbiology
    Publikationsdatum: 1999
    ZDB Id: 1483247-1
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 10
    Online-Ressource
    Online-Ressource
    American Chemical Society (ACS) ; 2000
    In:  Biochemistry Vol. 39, No. 47 ( 2000-11-01), p. 14504-14514
    In: Biochemistry, American Chemical Society (ACS), Vol. 39, No. 47 ( 2000-11-01), p. 14504-14514
    Materialart: Online-Ressource
    ISSN: 0006-2960 , 1520-4995
    RVK:
    Sprache: Englisch
    Verlag: American Chemical Society (ACS)
    Publikationsdatum: 2000
    ZDB Id: 1472258-6
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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