The Experts below are selected from a list of 5655 Experts worldwide ranked by ideXlab platform
Richard L Gallo - One of the best experts on this subject based on the ideXlab platform.
-
bacterial subversion of camp signalling inhibits Cathelicidin expression which is required for innate resistance to mycobacterium tuberculosis
The Journal of Pathology, 2017Co-Authors: Shashank Gupta, Richard L Gallo, Kathryn Winglee, William R BishaiAbstract:Antimicrobial peptides such as Cathelicidins are important components of innate immune defence against inhaled microorganisms, and have shown antimicrobial activity against Mycobacterium tuberculosis in in vitro models. Despite this, little is known about the regulation and expression of Cathelicidin during tuberculosis in vivo. We sought to determine whether the Cathelicidin-related antimicrobial peptide gene (Cramp), the murine functional homologue of the human Cathelicidin gene (CAMP or LL-37), is required for regulation of protective immunity during M. tuberculosis infection in vivo. We used Cramp-/- mice in a validated model of pulmonary tuberculosis, and conducted cell-based assays with macrophages from these mice. We evaluated the in vivo susceptibility of Cramp-/- mice to infection, and also dissected various pro-inflammatory immune responses against M. tuberculosis. We observed increased susceptibility of Cramp-/- mice to M. tuberculosis as compared with wild-type mice. Macrophages from Cramp-/- mice were unable to control M. tuberculosis growth in an in vitro infection model, were deficient in intracellular calcium influx, and were defective in stimulating T cells. Additionally, CD4+ and CD8+ T cells from Cramp-/- mice produced less interferon-β upon stimulation. Furthermore, bacterial-derived cAMP modulated Cathelicidin expression in macrophages. Our results demonstrate that Cathelicidin is required for innate resistance to M. tuberculosis in a relevant animal model and is a key mediator in regulation of the levels of pro-inflammatory cytokines by calcium and cyclic nucleotides. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
-
the antimicrobial peptide Cathelicidin modulates clostridium difficile associated colitis and toxin a mediated enteritis in mice
Gut, 2013Co-Authors: Tressia C Hing, David Q Shih, Ryan Ichikawa, Michelle Cheng, Jeremy J W Chen, Xinhua Chen, Ivy Ka Man Law, Robert M Najarian, Ciaran P Kelly, Richard L GalloAbstract:Background Clostridium difficile mediates intestinal inflammation by releasing toxin A (TxA), a potent enterotoxin. Cathelicidins ( Camp as gene name, LL-37 peptide in humans and mCRAMP peptide in mice) are antibacterial peptides that also posses anti-inflammatory properties. Objectives To determine the role of Cathelicidins in models of Clostridium difficile infection and TxA-mediated ileal inflammation and cultured human primary monocytes. Design Wild-type (WT) and mCRAMP-deficient ( Camp −/− ) mice were treated with an antibiotic mixture and infected orally with C difficile . Some mice were intracolonically given mCRAMP daily for 3 days. Ileal loops were also prepared in WT mice and treated with either saline or TxA and incubated for 4 h, while some TxA-treated loops were injected with mCRAMP. Results Intracolonic mCRAMP administration to C difficile -infected WT mice showed significantly reduced colonic histology damage, apoptosis, tissue myeloperoxidase (MPO) and tumour necrosis factor (TNF)α levels. Ileal mCRAMP treatment also significantly reduced histology damage, tissue apoptosis, MPO and TNFα levels in TxA-exposed ileal loops. WT and Camp −/− mice exhibited similar intestinal responses in both models, implying that C difficile /TxA-induced endogenous Cathelicidin may be insufficient to modulate C difficile /TxA-mediated intestinal inflammation. Both LL-37 and mCRAMP also significantly reduced TxA-induced TNFα secretion via inhibition of NF-κB phosphorylation. Endogenous Cathelicidin failed to control C difficile and/or toxin A-mediated inflammation and even intestinal Cathelicidin expression was increased in humans and mice. Conclusion Exogenous Cathelicidin modulates C difficile colitis by inhibiting TxA-associated intestinal inflammation. Cathelicidin administration may be a new anti-inflammatory treatment for C difficile toxin-associated disease.
-
The FASEB Journal • Research Communication Kallikrein-mediated proteolysis regulates the antimicrobial effects of Cathelicidins in skin
2013Co-Authors: Kenshi Yamasaki, Robert A Dorschner, Chrystelle Bonnart, Pascal Descargues, Jürgen Schauber, Alvin Coda, Henry Lin, Norman M. Schechter, Alain Hovnanian, Richard L GalloAbstract:ABSTRACT The presence of Cathelicidin antimicrobial peptides provides an important mechanism for prevention of infection against a wide variety of microbial pathogens. The activity of Cathelicidin is controlled by enzymatic processing of the proform (hCAP18 in humans) to a mature peptide (LL-37 in human neutrophils). In this study, elements important to the processing of Cathelicidin in the skin were examined. Unique Cathelicidin peptides distinct from LL-37 were identified in normal skin. Through the use of selective inhibitors, SELDI-TOF-MS, Western blot, and siRNA, the serine proteases stratum corneum tryptic enzyme (SCTE, kallikrein 5) and stratum corneum chymotryptic protease (SCCE, kallikrein 7) were shown to control activation of the human Cathelicidin precursor protein hCAP18 and also influence further processing to smaller peptides with alternate biological activity. The importance of this serine protease activity to antimicrobial activity in vivo was illustrated in SPINK5-deficent mice that lack the serine protease inhibitor LEKTI. Epidermal extracts of these animals show a significant increase in antimicrobial activity compared with controls, and immunoabsorption of Cathelicidin diminished antimicrobial activity. These observations demonstrate that the balance of proteolytic activity at an epithelial interface will control innate immune defense.—Yamasaki
-
Cathelicidin related antimicrobial peptide is required for effective lung mucosal immunity in gram negative bacterial pneumonia
Journal of Immunology, 2012Co-Authors: Melissa A Kovach, Xianying Zeng, Megan N Ballinger, Michael W. Newstead, Richard L Gallo, Urvashi Bhan, Bethany B Moore, Theodore J. StandifordAbstract:Cathelicidins are a family of endogenous antimicrobial peptides that exert diverse immune functions, including both direct bacterial killing and immunomodulatory effects. In this study, we examined the contribution of the murine Cathelicidin, Cathelicidin-related antimicrobial peptide (CRAMP), to innate mucosal immunity in a mouse model of Gram-negative pneumonia. CRAMP expression is induced in the lung in response to infection with Klebsiella pneumoniae. Mice deficient in the gene encoding CRAMP (Cnlp(-/-)) demonstrate impaired lung bacterial clearance, increased bacterial dissemination, and reduced survival in response to intratracheal K. pneumoniae administration. Neutrophil influx into the alveolar space during K. pneumoniae infection was delayed early but increased by 48 h in CRAMP-deficient mice, which was associated with enhanced expression of inflammatory cytokines and increased lung injury. Bone marrow chimera experiments indicated that CRAMP derived from bone marrow cells rather than structural cells was responsible for antimicrobial effects in the lung. Additionally, CRAMP exerted bactericidal activity against K. pneumoniae in vitro. Similar defects in lung bacterial clearance and delayed early neutrophil influx were observed in CRAMP-deficient mice infected with Pseudomonas aeruginosa, although this did not result in increased bacterial dissemination, increased lung injury, or changes in lethality. Taken together, our findings demonstrate that CRAMP is an important contributor to effective host mucosal immunity in the lung in response to Gram-negative bacterial pneumonia.
-
Antimicrobial peptides and the skin immune defense system.
The Journal of allergy and clinical immunology, 2009Co-Authors: Jürgen Schauber, Richard L GalloAbstract:Our skin is constantly challenged by microbes but is rarely infected. Cutaneous production of antimicrobial peptides (AMPs) is a primary system for protection, and expression of some AMPs further increases in response to microbial invasion. Cathelicidins are unique AMPs that protect the skin through 2 distinct pathways: (1) direct antimicrobial activity and (2) initiation of a host response resulting in cytokine release, inflammation, angiogenesis, and reepithelialization. Cathelicidin dysfunction emerges as a central factor in the pathogenesis of several cutaneous diseases, including atopic dermatitis, in which Cathelicidin is suppressed; rosacea, in which Cathelicidin peptides are abnormally processed to forms that induce inflammation; and psoriasis, in which Cathelicidin peptide converts self-DNA to a potent stimulus in an autoinflammatory cascade. Recent work identified vitamin D3 as a major factor involved in the regulation of Cathelicidin. Therapies targeting control of Cathelicidin and other AMPs might provide new approaches in the management of infectious and inflammatory skin diseases.
Phillip H Koeffler - One of the best experts on this subject based on the ideXlab platform.
-
human Cathelicidin antimicrobial peptide camp gene is a direct target of the vitamin d receptor and is strongly up regulated in myeloid cells by 1 25 dihydroxyvitamin d3
The FASEB Journal, 2005Co-Authors: Adrian F Gombart, Niels Borregaard, Phillip H KoefflerAbstract:The innate immune system of mammals provides a rapid response to repel assaults from numerous infectious agents including bacteria, viruses, fungi, and parasites. A major component of this system is a diverse combination of cationic antimicrobial peptides that include the α- and β-defensins and Cathelicidins. In this study, we show that 1,25-dihydroxyvitamin D3 and three of its analogs induced expression of the human Cathelicidin antimicrobial peptide (CAMP) gene. This induction was observed in acute myeloid leukemia (AML), immortalized keratinocyte, and colon cancer cell lines, as well as normal human bone marrow (BM) -derived macrophages and fresh BM cells from two normal individuals and one AML patient. The induction occurred via a consensus vitamin D response element (VDRE) in the CAMP promoter that was bound by the vitamin D receptor (VDR). Induction of CAMP in murine cells was not observed and expression of CAMP mRNA in murine VDR-deficient bone marrow was similar to wild-type levels. Comparison of ...
-
human Cathelicidin antimicrobial peptide camp gene is a direct target of the vitamin d receptor and is strongly up regulated in myeloid cells by 1 25 dihydroxyvitamin d3
The FASEB Journal, 2005Co-Authors: Adrian F Gombart, Niels Borregaard, Phillip H KoefflerAbstract:The innate immune system of mammals provides a rapid response to repel assaults from numerous infectious agents including bacteria, viruses, fungi, and parasites. A major component of this system is a diverse combination of cationic antimicrobial peptides that include the alpha- and beta-defensins and Cathelicidins. In this study, we show that 1,25-dihydroxyvitamin D3 and three of its analogs induced expression of the human Cathelicidin antimicrobial peptide (CAMP) gene. This induction was observed in acute myeloid leukemia (AML), immortalized keratinocyte, and colon cancer cell lines, as well as normal human bone marrow (BM) -derived macrophages and fresh BM cells from two normal individuals and one AML patient. The induction occurred via a consensus vitamin D response element (VDRE) in the CAMP promoter that was bound by the vitamin D receptor (VDR). Induction of CAMP in murine cells was not observed and expression of CAMP mRNA in murine VDR-deficient bone marrow was similar to wild-type levels. Comparison of mammalian genomes revealed evolutionary conservation of the VDRE in a short interspersed nuclear element or SINE in the CAMP promoter of primates that was absent in the mouse, rat, and canine genomes. Our findings reveal a novel activity of 1,25-dihydroxyvitamin D3 and the VDR in regulation of primate innate immunity.
Jürgen Schauber - One of the best experts on this subject based on the ideXlab platform.
-
The FASEB Journal • Research Communication Kallikrein-mediated proteolysis regulates the antimicrobial effects of Cathelicidins in skin
2013Co-Authors: Kenshi Yamasaki, Robert A Dorschner, Chrystelle Bonnart, Pascal Descargues, Jürgen Schauber, Alvin Coda, Henry Lin, Norman M. Schechter, Alain Hovnanian, Richard L GalloAbstract:ABSTRACT The presence of Cathelicidin antimicrobial peptides provides an important mechanism for prevention of infection against a wide variety of microbial pathogens. The activity of Cathelicidin is controlled by enzymatic processing of the proform (hCAP18 in humans) to a mature peptide (LL-37 in human neutrophils). In this study, elements important to the processing of Cathelicidin in the skin were examined. Unique Cathelicidin peptides distinct from LL-37 were identified in normal skin. Through the use of selective inhibitors, SELDI-TOF-MS, Western blot, and siRNA, the serine proteases stratum corneum tryptic enzyme (SCTE, kallikrein 5) and stratum corneum chymotryptic protease (SCCE, kallikrein 7) were shown to control activation of the human Cathelicidin precursor protein hCAP18 and also influence further processing to smaller peptides with alternate biological activity. The importance of this serine protease activity to antimicrobial activity in vivo was illustrated in SPINK5-deficent mice that lack the serine protease inhibitor LEKTI. Epidermal extracts of these animals show a significant increase in antimicrobial activity compared with controls, and immunoabsorption of Cathelicidin diminished antimicrobial activity. These observations demonstrate that the balance of proteolytic activity at an epithelial interface will control innate immune defense.—Yamasaki
-
Cathelicidin ll 37 an antimicrobial peptide with a role in inflammatory skin disease
Annals of Dermatology, 2012Co-Authors: Markus Reinholz, Thomas Ruzicka, Jürgen SchauberAbstract:Chronic inflammatory skin diseases such as atopic dermatitis, psoriasis or rosacea are very common. Although their exact pathogenesis is not completely understood all three diseases are characterized by dysregulation of cutaneous innate immunity. Cathelicidin LL-37 is an important effector molecule of innate immunity in the skin and atopic dermatitis, psoriasis or rosacea show defects in Cathelicidin expression, function or processing. In atopic dermatitis, Cathelicidin induction might be disturbed resulting in defective antimicrobial barrier function. In contrast, psoriasis is characterized by overexpression of Cathelicidin. However to date it is unclear whether pro- or anti-inflammatory functions of Cathelicidin predominate in lesional skin in psoriasis. In rosacea, Cathelicidin processing is disturbed resulting in peptide fragments causing inflammation, erythema and telangiectasias. In this review, the current evidence on the role of Cathelicidin LL-37 in the pathogenesis of inflammatory skin diseases will be outlined. As Cathelicidin LL-37 might also serve as a future treatment target potential novel treatment strategies for those diseases will be discussed.
-
vdr and mek erk dependent induction of the antimicrobial peptide Cathelicidin in keratinocytes by lithocholic acid
Molecular Immunology, 2009Co-Authors: Mark Peric, Thomas Ruzicka, Sarah Koglin, Yvonne Dombrowski, Kathrin Gross, Eva Bradac, Jürgen SchauberAbstract:Cathelicidin is an antimicrobial peptide (AMP) and signaling molecule in innate immunity and a direct target of 1,25-dihydroxyvitamin D3 (1,25D3) in primary human keratinocytes (NHEK). The expression of Cathelicidin is dysregulated in various skin diseases and its regulation differs depending on the epithelial cell type. The secondary bile acid lithocholic acid (LCA) is a ligand of the vitamin D receptor (VDR) and can carry out in vivo functions of vitamin D3. Therefore we analyzed Cathelicidin mRNA- and peptide expression levels in NHEK and colonic epithelial cells (Caco-2) after stimulation with LCA. We found increased expression of Cathelicidin mRNA and peptide in NHEK, in Caco-2 colon cells no effect was observed after LCA stimulation. The VDR as well as MEK-ERK signaled the upregulation of Cathelicidin in NHEK induced by LCA. Collectively, our data indicate that Cathelicidin induction upon LCA treatment differs in keratinocytes and colonic epithelial cells. Based on these observations LCA-like molecules targeting Cathelicidin could be designed for the treatment of cutaneous diseases that are characterized by disturbed Cathelicidin expression.
-
Antimicrobial peptides and the skin immune defense system.
The Journal of allergy and clinical immunology, 2009Co-Authors: Jürgen Schauber, Richard L GalloAbstract:Our skin is constantly challenged by microbes but is rarely infected. Cutaneous production of antimicrobial peptides (AMPs) is a primary system for protection, and expression of some AMPs further increases in response to microbial invasion. Cathelicidins are unique AMPs that protect the skin through 2 distinct pathways: (1) direct antimicrobial activity and (2) initiation of a host response resulting in cytokine release, inflammation, angiogenesis, and reepithelialization. Cathelicidin dysfunction emerges as a central factor in the pathogenesis of several cutaneous diseases, including atopic dermatitis, in which Cathelicidin is suppressed; rosacea, in which Cathelicidin peptides are abnormally processed to forms that induce inflammation; and psoriasis, in which Cathelicidin peptide converts self-DNA to a potent stimulus in an autoinflammatory cascade. Recent work identified vitamin D3 as a major factor involved in the regulation of Cathelicidin. Therapies targeting control of Cathelicidin and other AMPs might provide new approaches in the management of infectious and inflammatory skin diseases.
-
il 17a enhances vitamin d3 induced expression of Cathelicidin antimicrobial peptide in human keratinocytes
Journal of Immunology, 2008Co-Authors: Mark Peric, Richard L Gallo, Thomas Ruzicka, Sarah Koglin, Songmin Kim, Shin Morizane, Robert Besch, J C Prinz, Jürgen SchauberAbstract:Cathelicidin is strongly expressed in lesional skin in psoriasis and may play an important role as both an antimicrobial peptide and as an autoinflammatory mediator in this chronic skin disease. The mechanism of increased Cathelicidin in psoriatic keratinocytes is not known, but recent observations have found that psoriasis has abundant Th17 cells that produce IL-17A and IL-22. We found that human keratinocytes stimulated with supernatants from T cells isolated from lesional psoriatic skin increased expression of Cathelicidin when stimulated in the presence of 1,25-dihydroxyvitamin D(3) (1,25D(3)). This increase was signaled through the IL-17RA. In vitro, IL-17A, but not IL-22, enhanced Cathelicidin mRNA and peptide expression in keratinocytes dependent on the presence of 1,25D(3). At the same time, coincubation with 1,25D(3) blocked induction of human beta-defensin 2 (HBD2), IL-6, and IL-8, which are other target genes of IL-17A. Act1, an adaptor associated with IL-17RA and essential for IL-17A signaling, mediated Cathelicidin induction, as its suppression by small interfering RNA inhibited HBD2 and Cathelicidin. Both, 1,25D(3) and IL-17A signaled Cathelicidin induction through MEK-ERK. These results suggest that increased IL-17A in psoriatic skin increases Cathelicidin through a vitamin D(3)-, Act1-, and MEK-ERK-dependent mechanism. Therapy targeting this Cathelicidin-regulating system might be beneficial in patients suffering from psoriasis.
Donald Y M Leung - One of the best experts on this subject based on the ideXlab platform.
-
Cathelicidin deficiency predisposes to eczema herpeticum
The Journal of Allergy and Clinical Immunology, 2006Co-Authors: Michael D Howell, Cathy Wong, Tatjana Pavicic, Joanne E Streib, Mark Boguniewicz, Andreas Wollenberg, Michael J. Flaig, Donald Y M LeungAbstract:Background The Cathelicidin family of antimicrobial peptides is an integral component of the innate immune response that exhibits activity against bacterial, fungal, and viral pathogens. Eczema herpeticum (ADEH) develops in a subset of patients with atopic dermatitis (AD) because of disseminated infection with herpes simplex virus (HSV). Objective This study investigated the potential role of Cathelicidins in host susceptibility to HSV infection. Methods Glycoprotein D was measured by means of real-time RT-PCR as a marker of HSV replication in skin biopsy specimens and human keratinocyte cultures. Cathelicidin expression was evaluated in skin biopsy specimens from patients with AD (n = 10) without a history of HSV skin infection and from patients with ADEH (n = 10). Results The Cathelicidin peptide LL-37 (human Cathelicidin) exhibited activity against HSV in an antiviral assay, with significant killing (P Conclusion This study demonstrates that the Cathelicidin peptide LL-37 possesses antiviral activity against HSV and demonstrates the importance of variable skin expression of Cathelicidins in controlling susceptibility to ADEH. Additionally, serum IgE levels might be a surrogate marker for innate immune function and serve as a biomarker for which patients with AD are susceptible to ADEH. Clinical implications A deficiency of LL-37 might render patients with AD susceptible to ADEH. Therefore increasing production of skin LL-37 might prevent herpes infection in patients with AD.
-
Cathelicidin deficiency predisposes to eczema herpeticum
The Journal of Allergy and Clinical Immunology, 2006Co-Authors: Michael D Howell, Cathy Wong, Tatjana Pavicic, Joanne E Streib, Mark Boguniewicz, Andreas Wollenberg, Michael J. Flaig, Donald Y M LeungAbstract:Background The Cathelicidin family of antimicrobial peptides is an integral component of the innate immune response that exhibits activity against bacterial, fungal, and viral pathogens. Eczema herpeticum (ADEH) develops in a subset of patients with atopic dermatitis (AD) because of disseminated infection with herpes simplex virus (HSV). Objective This study investigated the potential role of Cathelicidins in host susceptibility to HSV infection. Methods Glycoprotein D was measured by means of real-time RT-PCR as a marker of HSV replication in skin biopsy specimens and human keratinocyte cultures. Cathelicidin expression was evaluated in skin biopsy specimens from patients with AD (n = 10) without a history of HSV skin infection and from patients with ADEH (n = 10). Results The Cathelicidin peptide LL-37 (human Cathelicidin) exhibited activity against HSV in an antiviral assay, with significant killing ( P −/− ) mouse skin (2.6 ± 0.5 pg HSV/pg GAPDH, P P r 2 = 0.46, P Conclusion This study demonstrates that the Cathelicidin peptide LL-37 possesses antiviral activity against HSV and demonstrates the importance of variable skin expression of Cathelicidins in controlling susceptibility to ADEH. Additionally, serum IgE levels might be a surrogate marker for innate immune function and serve as a biomarker for which patients with AD are susceptible to ADEH. Clinical implications A deficiency of LL-37 might render patients with AD susceptible to ADEH. Therefore increasing production of skin LL-37 might prevent herpes infection in patients with AD.
-
cytokine milieu of atopic dermatitis skin subverts the innate immune response to vaccinia virus
Immunity, 2006Co-Authors: Michael D Howell, Cathy Wong, Joanne E Streib, Mark Boguniewicz, Richard L Gallo, James F Jones, Donald Y M LeungAbstract:Atopic dermatitis (AD) is associated with eczema vaccinatum (EV), a disseminated viral skin infection that follows inoculation with vaccinia virus (VV). This study examined whether AD skin can control VV replication, and the role of IL-4 and IL-13 in modulating the human Cathelicidin LL-37, an antimicrobial peptide that kills VV. AD skin exhibited increased VV replication and decreased LL-37 expression compared to normal or psoriasis skin. IL-4/IL-13 enhanced VV replication while downregulating LL-37 in VV-stimulated keratinocytes. Neutralizing IL-4/IL-13 in AD skin augmented LL-37 and inhibited VV replication. Cathelicidins were induced via toll-like receptor-3 and were inhibited by IL-4/IL-13 through STAT-6. Skin from Cathelicidin-deficient mice exhibited reduced ability to control VV replication. Exogenous LL-37 controlled vaccinia viral replication in infected keratinocytes and AD skin explants. The current study demonstrates that Th2 cytokines enhance VV replication in AD skin by subverting the innate immune response against VV in a STAT-6-dependent manner.
-
structure function relationships among human Cathelicidin peptides dissociation of antimicrobial properties from host immunostimulatory activities
Journal of Immunology, 2005Co-Authors: Marissa H Braff, Anna Di Nardo, Cathy Wong, Joanne E Streib, Michael D Howell, Robert A Dorschner, Kenneth H Lin, Belen Lopezgarcia, Mi I A Hawkins, Donald Y M LeungAbstract:Cathelicidins and other antimicrobial peptides are deployed at epithelial surfaces to defend against infection. These molecules have broad-spectrum killing activity against microbes and can have effects on specific mammalian cell types, potentially stimulating additional immune defense through direct chemotactic activity or induction of cytokine release. In humans, the Cathelicidin hCAP18/LL-37 is processed to LL-37 in neutrophils, but on skin it can be further proteolytically processed to shorter forms. The influence of these Cathelicidin peptides on keratinocyte function is not known. In the current study, DNA microarray analysis and confirmatory protein analysis showed that LL-37 affects the expression of several chemokines and cytokines by keratinocytes. Analysis of a synthetic peptide library derived from LL-37 showed that antimicrobial activity against bacterial, fungal, and viral skin pathogens resides within specific domains of the parent peptide, but antimicrobial activity does not directly correlate with the ability to stimulate IL-8 production in keratinocytes. IL-8 release was induced by d- and l-amino acid forms of Cathelicidin and correlated with membrane permeability, suggesting that highly structure-specific binding to a cell surface receptor is not likely. However, this effect was inhibited by either pertussis toxin or AG1478, an epidermal growth factor receptor tyrosine kinase inhibitor, suggesting that Cathelicidin may indirectly stimulate multiple signaling pathways associated with cell surface receptors. Taken together, these observations suggest that proteolytic processing may alter the balance between Cathelicidin antimicrobial and host immunostimulatory functions.
-
selective killing of vaccinia virus by ll 37 implications for eczema vaccinatum
Journal of Immunology, 2004Co-Authors: Michael D Howell, Joanne E Streib, Richard L Gallo, James F Jones, Kevin O Kisich, Donald Y M LeungAbstract:Possible bioterrorism with smallpox has led to the resumption of smallpox (vaccinia virus) immunization. One complication, eczema vaccinatum, occurs primarily in patients with atopic dermatitis (AD). Skin lesions of patients with AD, but not psoriasis, is deficient in the Cathelicidin antimicrobial peptide (LL-37) and human beta-defensin-2 (HBD-2). We hypothesized that this defect may explain the susceptibility of patients with AD to eczema vaccinatum. The Wyeth vaccine strain of vaccinia virus was incubated with varying concentrations of human (LL-37) and murine (CRAMP) Cathelicidins, human alpha-defensin (HBD-1, HBD-2), and a control peptide. Outcomes included quantification of viral PFU, vaccinia viral gene expression by quantitative real-time RT-PCR, and changes in virion structure by transmission electron microscopy. CRAMP knockout mice and control animals were inoculated by skin pricks with 2 x 10(5) PFU of vaccinia and examined daily for pox development. Physiologic amounts of human and murine Cathelicidins (10-50 micro M), but not human defensins, which had antibacterial activity, resulted in the in vitro reduction of vaccinia viral plaque formation (p < 0.0001), vaccinia mRNA expression (p < 0.001), and alteration of vaccinia virion structure. In vivo vaccinia pox formation occurred in four of six CRAMP knockout animals and in only one of 15 control mice (p < 0.01). These data support a role for Cathelicidins in the inhibition of orthopox virus (vaccinia) replication both in vitro and in vivo. Susceptibility of patients with AD to eczema vaccinatum may be due to a deficiency of Cathelicidin.
Niels Borregaard - One of the best experts on this subject based on the ideXlab platform.
-
PHAGOCYTES Human Cathelicidin, hCAP-18, is processed to the antimicrobial peptide LL-37 by extracellular cleavage with proteinase 3
2016Co-Authors: Ole E Sorensen, Per Follin, Anders H Johnsen, Jero Calafat, Pieter S Hiemstra, Ra Tjabringa, Niels BorregaardAbstract:Cathelicidins are a family of antimicrobial proteins found in the peroxidase-nega-tive granules of neutrophils. The known biologic functions reside in the C-termi-nus, which must be cleaved from the holoprotein to become active. Bovine and porcine Cathelicidins are cleaved by elas-tase from the azurophil granules to yield the active antimicrobial peptides. The aim of this study was to identify the physiolog-ical setting for cleavage of the only hu-man Cathelicidin, hCAP-18, to liberate the antibacterial and cytotoxic peptide LL-37 and to identify the protease responsible for this cleavage. Immunoelectron micros-copy demonstrated that both hCAP-18 and azurophil granule proteins were present in the phagolysosome. Immuno-blotting revealed no detectable cleavage of hCAP-18 in cells after phagocytosis. In contrast, hCAP-18 was cleaved to gener-ate LL-37 in exocytosed material. Of the 3 known serine proteases from azurophil granules, proteinase 3 was solely respon-sible for cleavage of hCAP-18 after exocy-tosis. This is the first detailed study de-scribing the generation of a human antimicrobial peptide from a promicrobici-dal protein, and it demonstrates that the generation of active antimicrobial pep-tides from common proproteins occurs differently in related species. (Blood. 2001
-
human Cathelicidin antimicrobial peptide camp gene is a direct target of the vitamin d receptor and is strongly up regulated in myeloid cells by 1 25 dihydroxyvitamin d3
The FASEB Journal, 2005Co-Authors: Adrian F Gombart, Niels Borregaard, Phillip H KoefflerAbstract:The innate immune system of mammals provides a rapid response to repel assaults from numerous infectious agents including bacteria, viruses, fungi, and parasites. A major component of this system is a diverse combination of cationic antimicrobial peptides that include the α- and β-defensins and Cathelicidins. In this study, we show that 1,25-dihydroxyvitamin D3 and three of its analogs induced expression of the human Cathelicidin antimicrobial peptide (CAMP) gene. This induction was observed in acute myeloid leukemia (AML), immortalized keratinocyte, and colon cancer cell lines, as well as normal human bone marrow (BM) -derived macrophages and fresh BM cells from two normal individuals and one AML patient. The induction occurred via a consensus vitamin D response element (VDRE) in the CAMP promoter that was bound by the vitamin D receptor (VDR). Induction of CAMP in murine cells was not observed and expression of CAMP mRNA in murine VDR-deficient bone marrow was similar to wild-type levels. Comparison of ...
-
human Cathelicidin antimicrobial peptide camp gene is a direct target of the vitamin d receptor and is strongly up regulated in myeloid cells by 1 25 dihydroxyvitamin d3
The FASEB Journal, 2005Co-Authors: Adrian F Gombart, Niels Borregaard, Phillip H KoefflerAbstract:The innate immune system of mammals provides a rapid response to repel assaults from numerous infectious agents including bacteria, viruses, fungi, and parasites. A major component of this system is a diverse combination of cationic antimicrobial peptides that include the alpha- and beta-defensins and Cathelicidins. In this study, we show that 1,25-dihydroxyvitamin D3 and three of its analogs induced expression of the human Cathelicidin antimicrobial peptide (CAMP) gene. This induction was observed in acute myeloid leukemia (AML), immortalized keratinocyte, and colon cancer cell lines, as well as normal human bone marrow (BM) -derived macrophages and fresh BM cells from two normal individuals and one AML patient. The induction occurred via a consensus vitamin D response element (VDRE) in the CAMP promoter that was bound by the vitamin D receptor (VDR). Induction of CAMP in murine cells was not observed and expression of CAMP mRNA in murine VDR-deficient bone marrow was similar to wild-type levels. Comparison of mammalian genomes revealed evolutionary conservation of the VDRE in a short interspersed nuclear element or SINE in the CAMP promoter of primates that was absent in the mouse, rat, and canine genomes. Our findings reveal a novel activity of 1,25-dihydroxyvitamin D3 and the VDR in regulation of primate innate immunity.
-
isolation of human cationic antimicrobial protein 18 from seminal plasma and its association with prostasomes
Human Reproduction, 2002Co-Authors: Emma Andersson, Ole E Sorensen, Niels Borregaard, Birgitta Frohm, Arne Egesten, Johan MalmAbstract:BACKGROUND: Cathelicidins are a group of antibiotic peptides with broad antimicrobial activity. They are considered to be an essential part of the innate immune system. The only known human Cathelicidin is the human cationic antimicrobial protein (hCAP-18), from which the antimicrobial peptide LL-37 is released. METHODS AND RESULTS: In the present study, we purified hCAP-18 from seminal plasma and confirmed its identity by N-terminal amino acid sequencing. Gel filtration of seminal plasma showed the presence of hCAP-18 in both a low and a high molecular weight peak. Fractions corresponding to the high molecular form of hCAP-18 also contained dipeptidyl peptidase IV (CD26), a prostasome marker. This finding suggested that hCAP-18 found in fractions corresponding to high molecular weight molecules, is prostasome-associated. Flow cytometry confirmed the association of hCAP-18 with prostasomes and indicated that the molecule is surface bound. Western blot showed the presence of intact hCAP-18 in sperm, prostasomes and ultracentrifuged seminal plasma. CONCLUSIONS: These findings suggest that hCAP-18 may have an important role in antimicrobial defence during human reproduction. The binding of hCAP-18 to prostasomes indicates that protasomes can serve as a reservoir of this precursor of the antibiotic peptide LL-37.
-
human Cathelicidin hcap 18 is processed to the antimicrobial peptide ll 37 by extracellular cleavage with proteinase 3
Blood, 2001Co-Authors: Ole E Sorensen, Per Follin, Anders H Johnsen, Jero Calafat, Sandra G Tjabringa, Pieter S Hiemstra, Niels BorregaardAbstract:Cathelicidins are a family of antimicrobial proteins found in the peroxidase-negative granules of neutrophils. The known biologic functions reside in the C-terminus, which must be cleaved from the holoprotein to become active. Bovine and porcine Cathelicidins are cleaved by elastase from the azurophil granules to yield the active antimicrobial peptides. The aim of this study was to identify the physiological setting for cleavage of the only human Cathelicidin, hCAP-18, to liberate the antibacterial and cytotoxic peptide LL-37 and to identify the protease responsible for this cleavage. Immunoelectron microscopy demonstrated that both hCAP-18 and azurophil granule proteins were present in the phagolysosome. Immunoblotting revealed no detectable cleavage of hCAP-18 in cells after phagocytosis. In contrast, hCAP-18 was cleaved to generate LL-37 in exocytosed material. Of the 3 known serine proteases from azurophil granules, proteinase 3 was solely responsible for cleavage of hCAP-18 after exocytosis. This is the first detailed study describing the generation of a human antimicrobial peptide from a promicrobicidal protein, and it demonstrates that the generation of active antimicrobial peptides from common proproteins occurs differently in related species.