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  • 1
    Keywords: CELLS ; ENDOTHELIAL-CELLS ; INHIBITOR ; CELL ; IN-VIVO ; PATHWAY ; MICE ; MACROPHAGES ; MECHANISM ; STAGE ; PERMEABILITY ; ORIGIN ; BASEMENT-MEMBRANE ; INCREASE ; MATRIX METALLOPROTEINASES ; MMP-9 ; PROSTAGLANDIN SYNTHESIS ; cyclooxygenase ; PROSTAGLANDIN E-2 ; macrophage ; E ; ENDOTHELIAL-CELL ; DEPLETION ; peritonitis ; METALLOPROTEINASE ; CYSTEINYL-LEUKOTRIENES ; gelatinase B ; MAST-CELLS ; peritoneal inflammation ; VASCULAR-PERMEABILITY ; metalloproteinase-9 ; prostaglandin ; SELECTIVE-INHIBITION ; TARGETED GENE DISRUPTION ; vasopermeability ; ZYMOSAN
    Abstract: Increased vascular permeability leading to vascular leakage is a central feature of all inflammatory reactions and is critical for the formation of an inflammatory exudate. The leakage occurs because of gap formation between endothelial cells and breakdown of the basement membrane barriers. The present study aimed to investigate the role of gelatinase B [matrix metalloproteinase 9 (MMP-9)], known to be involved in neutrophil exudation, in changes of vascular permeability at the early stages of acute zymosan peritonitis. We show that although MMP-9 is being released already within the first minutes of peritonitis, its lack, induced pharmacologically or genetically, does not decrease but rather increases vasopermeability. In mice treated with an inhibitor of gelatinases (A and B), a tendency to increased vasopermeability existed, and in MMP-9-/- mice [knockout (KO)], the difference was statistically significant in comparison with their controls. Moreover, in intact KO mice, significantly augmented production of prostaglandin E-2 (PGE(2)) of cyclooxygenase I (COX-1) origin was detected, anti depletion of peritoneal macrophages, but not mast cells, decreased vasopermeability in KO mice. Thus, the increase of vasopermeability observed on KO mice is a result of the increased production of COX-1-derived PGE2 by peritoneal macrophages. We conclude that genetic deficiency in gelatinase B might lead to the development of a compensatory mechanism involving the COX pathway
    Type of Publication: Journal article published
    PubMed ID: 16684893
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  • 2
    Keywords: CELLS ; EXPRESSION ; DISEASE ; POPULATION ; PROTEIN ; MICE ; MOUSE ; inflammation ; NEUTROPHILS ; INHIBITORS ; ELISA ; PHASE ; prostaglandins ; cyclooxygenase ; peritoneal inflammation ; EARLY VASCULAR-PERMEABILITY ; GENE DISRUPTION ; ZYMOSAN PERITONITIS ; GELATINASE B/MATRIX METALLOPROTEINASE-9 ; resident peritoneal leukocytes
    Abstract: Cyclooxygenases (COXs) play important roles during inflammation. While reports on COX-2 function in inflammation preceded those on COX-1, it is now well established that both isoforms participate in this process. During inflammation, COX expression was reported in inflammatory leukocytes, but much less is known about their presence in tissue- resident leukocytes. The aim was thus to verify the expression and activity of the COX isoforms in resident peritoneal mast cells and macrophages during acute peritonitis. Zymosan peritoneal inflammation was induced in C57BL/6J mice and COX-1 and COX-2 expression was evaluated by RT-PCR (mRNA level) and immunocytochemistry (protein level). COX activity was assessed by a specific assay and prostaglandin production by ELISA. Furthermore, some mice were selectively depleted of either peritoneal mast cells or macrophages and then COX activity was determined. The study revealed that both COXs are expressed/active at the peak of inflammation, but COX-2 predominates during resolution. The expressions of the COXs were detectable in both populations of resident peritoneal leukocytes. In peritoneal macrophages both isoforms were active even during the late phases of peritonitis and the cells significantly contributed to PGE(2) and PGD(2) synthesis. The most striking observation was that resident macrophages are critical for PGD(2) production during the resolution of inflammation. This study documents that both COX isoforms participate in all stages of acute inflammation and that tissue-resident leukocytes, especially macrophages, are important sites of COX-1/COX-2 expression and prostaglandin synthesis
    Type of Publication: Journal article published
    PubMed ID: 19885646
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  • 3
    Keywords: ENDOTHELIAL-CELLS ; CD8(+) T-CELLS ; DENDRITIC CELLS ; TOLERANCE ; IMMUNE-RESPONSE ; MOUSE MODEL ; INFECTIONS ; EXOGENOUS ANTIGEN ; HEPATITIS-B-VIRUS ; LIVER-DAMAGE
    Abstract: Viruses can escape cytotoxic T cell (CTL) immunity by avoiding presentation of viral components via endogenous MHC class I antigen presentation in infected cells. Cross-priming of viral antigens circumvents such immune escape by allowing noninfected dendritic cells to activate virus-specific CTLs, but they remain ineffective against infected cells in which immune escape is functional. Here, we show that cross-presentation of antigen released from adenovirus-infected hepatocytes by liver sinusoidal endothelial cells stimulated cross-primed effector CTLs to release tumor necrosis factor (TNF), which killed virus-infected hepatocytes through caspase activation. TNF receptor signaling specifically eliminated infected hepatocytes that showed impaired anti-apoptotic defense. Thus, CTL immune surveillance against infection relies on two similarly important but distinct effector functions that are both MHC restricted, requiring either direct antigen recognition on target cells and canonical CTL effector function or cross-presentation and a noncanonical effector function mediated by TNF.
    Type of Publication: Journal article published
    PubMed ID: 22939982
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  • 4
    Keywords: CELLS ; EXPRESSION ; CELL ; TISSUE ; MICE ; RELEASE ; TIME ; MACROPHAGES ; treatment ; TARGET ; STAGE ; DECREASE ; leukocyte ; NETHERLANDS ; KINETICS ; TARGETS ; inflammation ; GELATINASE-B ; mast cells ; INFILTRATION ; MATRIX METALLOPROTEINASES ; PHASE ; MMP-9 ; TISSUE INHIBITOR ; MURINE MACROPHAGES ; E ; immunology ; DEPLETION ; peritonitis ; METALLOPROTEINASE ; CYSTEINYL-LEUKOTRIENES ; gelatinase B ; MAST-CELLS ; peritoneal inflammation ; metalloproteinase-9 ; ZYMOSAN ; POINT ; ACUTE-INFLAMMATION ; EARLY VASCULAR-PERMEABILITY ; MATRIX-METALLOPROTEINASE-9 MMP-9 ; metalloproteinase 9 ; NEUTROPHIL MIGRATION ; resident leukocytes
    Abstract: Metalloproteinase 9 (MMP-9) is crucial for normal neutrophil infiltration into zymosan-inflamed peritoneum. During the course of zymosan peritonitis MMP-9 is produced in a biphasic-manner as its presence is detectable as early as 30 min post zymosan and then between 2 and 8 h of inflammation. As inflammatory leukocytes were shown to produce MMP-9 we asked if also resident leukocytes, mast cells and macrophages, contribute to its production. And furthermore, if their contribution is limited only to the early phase of inflammation or extends to the later stages. For this purpose some mice were depleted of either resident macrophages or functional mast cells and expression of MMP-9 in peritoneal leukocytes and its release to the exudate were monitored. It turned out that depletion of peritoneal macrophages decreased both MMP-9 content in the leukocytes and its release to the inflammatory exudate at 30 min and 6 h of peritonitis. The functional depletion of mast cells also caused a significant decrease in the production/release of MMP-9 that was especially apparent at the early time point (30 min). Moreover, the study shows concomitant kinetics of MMP-9 expression in leukocytes and its release to the exudatory fluid. The findings indicate that resident tissue leukocytes, and among them especially macrophages, constitute an important source of MMP-9 during acute peritoneal inflammation. Overall, the study shows that resident tissue leukocytes, mostly macrophages, constitute an important cellular source(s) of inflammation-related factors and should be regarded as possible targets of anti-inflammatory treatment. (C) 2007 Elsevier B.V. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 17826846
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  • 5
    Abstract: Innate immune activation is essential to mount an effective antiviral response and to prime adaptive immunity. Although a crucial role of CD169(+) cells during vesicular stomatitis virus (VSV) infections is increasingly recognized, factors regulating CD169(+) cells during viral infections remain unclear. Here, we show that tumor necrosis factor is produced by CD11b(+) Ly6C(+) Ly6G(+) cells following infection with VSV. The absence of TNF or TNF receptor 1 (TNFR1) resulted in reduced numbers of CD169(+) cells and in reduced type I interferon (IFN-I) production during VSV infection, with a severe disease outcome. Specifically, TNF triggered RelA translocation into the nuclei of CD169(+) cells; this translocation was inhibited when the paracaspase MALT-1 was absent. Consequently, MALT1 deficiency resulted in reduced VSV replication, defective innate immune activation, and development of severe disease. These findings indicate that TNF mediates the maintenance of CD169(+) cells and innate and adaptive immune activation during VSV infection.IMPORTANCE Over the last decade, strategically placed CD169(+) metallophilic macrophages in the marginal zone of the murine spleen and lymph nodes (LN) have been shown to play a very important role in host defense against viral pathogens. CD169(+) macrophages have been shown to activate innate and adaptive immunity via "enforced virus replication," a controlled amplification of virus particles. However, the factors regulating the CD169(+) macrophages remain to be studied. In this paper, we show that after vesicular stomatitis virus infection, phagocytes produce tumor necrosis factor (TNF), which signals via TNFR1, and promote enforced virus replication in CD169(+) macrophages. Consequently, lack of TNF or TNFR1 resulted in defective immune activation and VSV clearance.
    Type of Publication: Journal article published
    PubMed ID: 29142134
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  • 6
    Keywords: IN-VIVO ; NF-KAPPA-B ; TNF-ALPHA ; INDUCED CELL-DEATH ; MEDIATED APOPTOSIS ; COMPENSATORY PROLIFERATION ; IKK-BETA ; CHRONIC INTESTINAL INFLAMMATION ; INDEPENDENT PATHWAY ; JNK ACTIVATION
    Abstract: As a catalytically inactive homolog of caspase-8, a proapoptotic initiator caspase, c-FLIP blocks apoptosis by binding to and inhibiting caspase-8. The transcription factor nuclear factor kappaB (NF-kappaB) plays a pivotal role in maintaining the homeostasis of the intestine and the liver by preventing death receptor-induced apoptosis, and c-FLIP plays a role in the NF-kappaB-dependent protection of cells from death receptor signaling. Because c-Flip-deficient mice die in utero, we generated conditional c-Flip-deficient mice to investigate the contribution of c-FLIP to homeostasis of the intestine and the liver at developmental and postnatal stages. Intestinal epithelial cell (IEC)- or hepatocyte-specific deletion of c-Flip resulted in perinatal lethality as a result of the enhanced apoptosis and programmed necrosis of the IECs and the hepatocytes. Deficiency in the gene encoding tumor necrosis factor-alpha (TNF-alpha) receptor 1 (Tnfr1) partially rescued perinatal lethality and the development of colitis in IEC-specific c-Flip-deficient mice but did not rescue perinatal lethality in hepatocyte-specific c-Flip-deficient mice. Moreover, adult mice with interferon (IFN)-inducible deficiency in c-Flip died from hepatitis soon after depletion of c-FLIP. Pretreatment of IFN-inducible c-Flip-deficient mice with a mixture of neutralizing antibodies against TNF-alpha, Fas ligand (FasL), and TNF-related apoptosis-inducing ligand (TRAIL) prevented hepatitis. Together, these results suggest that c-FLIP controls the homeostasis of IECs and hepatocytes by preventing cell death induced by TNF-alpha, FasL, and TRAIL.
    Type of Publication: Journal article published
    PubMed ID: 23250397
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  • 7
    Keywords: CELLS ; EXPRESSION ; INHIBITOR ; CELL ; IN-VIVO ; MODEL ; POPULATION ; PROTEIN ; ACCUMULATION ; MICE ; MACROPHAGES ; MEMBRANE ; MIGRATION ; POPULATIONS ; inflammation ; GELATINASE-B ; mast cells ; MATRIX ; ACUTE LUNG INJURY ; BASEMENT-MEMBRANE ; MATRIX METALLOPROTEINASES ; DEFICIENT MICE ; macrophage ; METALLOPROTEINASES ; gelatinase B ; MAST-CELLS ; peritoneal inflammation ; EARLY VASCULAR-PERMEABILITY ; EXTRACELLULAR TRAPS ; MATRIX METALLOPROTEASE-9 ; ZYMOSAN-INDUCED PERITONITIS
    Abstract: Extracellular proteolysis of basement membranes and matrix is required for leukocyte diapedesis and migration to the inflammatory focus. Neutrophil elastase (NE) and matrix metalloproteinases (MMPs) are among the enzymes involved in these processes, as shown in mice genetically deprived of such enzymes. However, studies with MMP-9(-/-) mice revealed that albeit neutrophil influx is impaired initially in these animals versus controls, neutrophilia is subsequently augmented during later stages of zymosan peritonitis. MMP-9 as a MMP and NE as a serine protease belong to different enzyme classes. As MMP-9 and NE are produced by neutrophils and have similar biological effects on matrix remodeling, it was evaluated whether enhanced NE activity might compensate for the lack of MMP-9. In genetically uncompromised mice, two waves of NE expression and activity during zymosan peritonitis were observed in inflammatory neutrophils and macrophages at the time of influx of the respective cell populations into the peritoneum. Additionally, NE expression was associated with the activity of resident peritoneal mast cells and macrophages, as their depletion reduced NE activity. Most importantly, the NE mRNA and protein expression and activity were enhanced significantly in MMP-9(-/-) mice during late stages of zymosan peritonitis. In addition, the application of a selective NE inhibitor restrained enhanced neutrophil accumulation significantly. In conclusion, during acute peritoneal inflammation, NE expression and activity increase gradually, facilitating leukocyte influx. Moreover, increased NE activity might compensate for a genetic lack of MMP-9 (as detected in MMP-9(-/-) mice), resulting in delayed accumulation of neutrophils during late zymosan peritonitis. J. Leukoc. Biol. 85: 374-381; 2009
    Type of Publication: Journal article published
    PubMed ID: 19088179
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  • 8
    Keywords: ANGIOGENESIS ; CANCER ; PROGRESSION ; METASTASIS ; SQUAMOUS-CELL CARCINOMAS ; INFLAMMATORY-BOWEL-DISEASE ; PSORIASIS ; TUMOR-ASSOCIATED MACROPHAGES ; FACTOR VEGF ; FLT-1
    Abstract: Inflammation contributes to tumour growth, invasion and angiogenesis. We investigated the contribution of macrophages and their polarization to tumour progression in a model of VEGF-A-induced skin carcinogenesis. Transfection of the human non-tumourigenic keratinocyte cell line HaCaT with murine VEGF-A leads to malignant tumour growth in vivo. The resulting tumours are characterized by extensive vascularization, invasive growth and high numbers of M2-polarized macrophages that crucially contribute to the establishment of the malignant phenotype. Accordingly, macrophage depletion from tumour-bearing animals resulted in reduced tumour growth, inhibition of invasion, decreased proliferation and reduced angiogenesis. In vitro, VEGF-A exerted a chemo-attracting effect on macrophages, but did not induce M2 polarization. We identified IL-4 and IL-10 as the factors involved in M2 polarization. These factors were produced by tumour cells (IL-10) and macrophages (IL-4) in vivo. Addition of recombinant IL-4 and IL-10 in vitro induced a pro-invasive M2 macrophage phenotype and inhibition of the IL-4 receptor in vivo blocked M2 polarization of macrophages, resulting in a less aggressive tumour phenotype. Thus, we provide evidence that M2 macrophages are crucial for the development of VEGF-A-induced skin tumours and that VEGF-A contributes to malignant tumour growth, not only by enhancing angiogenesis but also by establishing an anti-inflammatory microenvironment. However, VEGF-A alone is not sufficient to create a tumour-promoting microenvironment and requires the presence of IL-4 and IL-10 to induce M2 polarization of macrophages. Copyright (c) 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
    Type of Publication: Journal article published
    PubMed ID: 22262122
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  • 9
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  58. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie e.V. (DGNC); 20070426-20070429; Leipzig; DOCP 086 /20070411/
    Publication Date: 2007-04-04
    Keywords: adenosine ; microglia ; glioblastoma ; Adenosin ; Mikroglia ; Glioblastom ; ddc: 610
    Language: English
    Type: conferenceObject
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  • 10
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    German Medical Science GMS Publishing House; Düsseldorf
    In:  58. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie e.V. (DGNC); 20070426-20070429; Leipzig; DOCP 075 /20070411/
    Publication Date: 2007-04-04
    Keywords: serotonin ; microglia ; glioblastoma ; Serotonin ; Mikroglia ; Glioblastom ; ddc: 610
    Language: English
    Type: conferenceObject
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