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  • 1
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; tumor ; CELL ; Germany ; PROTEINS ; transcription ; TISSUE ; TUMORS ; MICE ; ACTIVATION ; COMPLEX ; LIGAND ; RESPONSES ; COMPLEXES ; CUTTING EDGE ; IFN-GAMMA ; MACROPHAGES ; TRANSCRIPTION FACTOR ; AP-1 ; TISSUES ; SKIN ; TARGET ; STRESS ; STRESS-RESPONSE ; LIGANDS ; NATURAL-KILLER-CELLS ; NK cells ; CD8(+) ; IMMUNE-RESPONSE ; CELL-SURFACE ; RE ; TUMORIGENESIS ; RHEUMATOID-ARTHRITIS ; LEVEL ; MICE LACKING JUNB ; immunology ; TRANSCRIPTION FACTOR AP-1 ; NKG2D RECEPTOR
    Abstract: The activating receptor NKG2D and its ligands RAE-1 play an important role in the NK, gamma delta(+), and CD8(+) T cell-mediated immune response to tumors. Expression levels of RAE-1 on target cells have to be tightly controlled to allow immune cell activation against tumors but to avoid destruction of healthy tissues. In this study, we report that cell surface expression of RAE-1 epsilon is greatly enhanced on cells lacking JunB, a subunit of the transcription complex AP-1. Furthermore, tissue-specific junB knockout mice respond to 12-O-tetradecanoyl-phorbol-13-acetate, a potent AP-1 activator, with markedly increased and sustained epidermal RAE-1 epsilon expression. Accordingly, junB-deficient cells are efficiently killed via NKG2D by NK cells and induce IFN-gamma production. Our data indicate that the transcription factor AP-1, which is involved in tumorigenesis and cellular stress responses, regulates RAE-1 epsilon. Thus, up-regulated RAE-1 epsilon expression due to low levels of JunB could alert immune cells to tumors and stressed cells
    Type of Publication: Journal article published
    PubMed ID: 16365389
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  • 2
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    Oncogene 27 (45), 5944-5958 
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; tumor ; CELL ; Germany ; PATHWAY ; DISTINCT ; TISSUE ; TUMORS ; LINES ; TIME ; ACTIVATION ; LIGAND ; RESPONSES ; CUTTING EDGE ; MECHANISM ; TISSUES ; CD8(+) T-CELLS ; DENDRITIC CELLS ; mechanisms ; BIOLOGY ; CELL-LINES ; DOWN-REGULATION ; MOLECULAR-BIOLOGY ; TARGET ; genetics ; CELL-LINE ; LINE ; ONCOGENE ; LIGANDS ; NK cells ; NKG2D ; RAE-1 ; STRATEGIES ; CD8(+) ; immune response ; IMMUNE-RESPONSE ; IMMUNITY ; HEALTHY ; heredity ; TUMOR-CELL-LINES ; tumor immunology ; signaling ; molecular biology ; molecular ; ONCOLOGY ; review ; RE ; GAMMA ; ACUTE MYELOID-LEUKEMIA ; TUMOR TISSUE ; LEVEL ; immunology ; ENGLAND ; NKG2D RECEPTOR ; UP-TO-DATE ; response ; ANTITUMOR RESPONSES ; CELL BIOLOGY ; HUMAN HEPATOCELLULAR CARCINOMAS ; NATURAL-KILLER-CELL ; MHC-CLASS-I ; natural killer ; ACTIVATING RECEPTOR ; MIC-A ; NKG2D ligands ; RETINOIC-ACID ; ULBP
    Abstract: The activating receptor NKG2D (natural-killer group 2, member D) and its ligands play an important role in the NK, gamma delta(+) and CD8(+) T-cell-mediated immune response to tumors. Ligands for NKG2D are rarely detectable on the surface of healthy cells and tissues, but are frequently expressed by tumor cell lines and in tumor tissues. It is evident that the expression levels of these ligands on target cells have to be tightly regulated to allow immune cell activation against tumors, but at the same time avoid destruction of healthy tissues. Importantly, it was recently discovered that another safeguard mechanism controlling activation via the receptor NKG2D exists. It was shown that NKG2D signaling is coupled to the IL-15 receptor pathway in a cell-specific manner suggesting that priming of NKG2D-mediated activation depends on the cellular microenvironment and the distinct cellular context. This review will provide a broad overview of our up-to-date knowledge of the NKG2D receptor and its ligands in the context of tumor immunology. Strategies to amplify NKG2D-mediated antitumor responses and counteract tumor immune escape mechanisms will be discussed
    Type of Publication: Journal article published
    PubMed ID: 18836475
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  • 3
    Keywords: brain ; EXPRESSION ; Germany ; GENE ; GENE-EXPRESSION ; GENES ; transcription ; LINES ; MICE ; gene transfer ; SEQUENCE ; TARGET ; TRANSGENIC MICE ; gene expression ; PROMOTER ; ELEMENTS ; NUMBER ; LINE ; IN-SITU HYBRIDIZATION ; cytochrome P450 ; TRANSCRIPTS ; ESTROGEN ; LEVEL ; ENZYME ; correlation ; ESTROGEN BIOSYNTHESIS ; ANDROGEN ; RNA EXPRESSION ; lacZ ; MESSENGER-RIBONUCLEIC-ACID ; ADULT-RAT BRAIN ; aromatase cytochrome P450 ; AROMATASE CYTOCHROME-P450 ; EC 1.14.14.1 ; ENCODING GENE ; HYPOTHALAMUS
    Abstract: Cyp19 encodes the key enzyme of estrogen biosynthesis, aromatase cytochrome P450. In mice it is mainly expressed in the ovary and brain, where transcription is directed by a distal, brain-specific promoter (P-br). In order to map functional sequence elements of P-br, portions of various length (0.2, 1.0, and 1.7 [kb]) were fused to a lacZ reporter gene and analyzed in transgenic mice. Numbers of integrated reporter genes varied from 1 to 23 copies in different transgenic lines. These copy numbers however did not show any correlation to the levels of transgene expression. All of the constructs were found being expressed in the olfactory bulb, limbic cortex, amygdala, and hypothalamus. Additional expression in thalamic nuclei, bed nucleus of stria terminalis, and dorsal mesencephalon was found in transgenic lines with constructs 1.0 and 1.7, and expression in septal and preoptic nuclei was only found with construct 1.7. The data demonstrate that 0.2 kb Of Pbr target reporter gene expression to specific brain areas. The data also strongly suggest that the sequence between 0.2 and 1.7 kb upstream, is necessary for expression in additional areas. However even 1.7 kb of P-br are not sufficient to consistently mimic the accurate expression pattern of Cyp19. (c) 2006 Elsevier Ltd. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 17079138
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  • 4
    Keywords: RECEPTOR ; CANCER ; CELLS ; IN-VITRO ; BLOOD ; CELL ; Germany ; IN-VIVO ; THERAPY ; VITRO ; VIVO ; MICE ; PATIENT ; ACTIVATION ; LIGAND ; RESPONSES ; CUTTING EDGE ; IFN-GAMMA ; IMPACT ; CD8(+) T-CELLS ; T cell ; T-CELL ; LYMPHOMA ; DESIGN ; NATURAL-KILLER-CELLS ; NK cells ; CANCER-PATIENTS ; immune response ; IMMUNE-RESPONSE ; REVEALS ; CANCER PATIENTS ; ANTITUMOR IMMUNITY ; HUMAN DENDRITIC CELLS ; RE ; THERAPIES ; T-CELL-ACTIVATION ; interaction ; SUPPRESSOR ; USA ; TUMOR-BEARING MICE ; NKG2D RECEPTOR ; NOV ; response ; NATURAL-KILLER-CELL ; Myeloid cell ; myeloid cells ; myeloid-derived suppressor cells ; SUPPRESSOR-CELLS ; SUPPRESSES ; KILLER-CELLS ; natural killer ; NK-CELLS ; NK CELL ACTIVATION ; ACTIVATING RECEPTOR ; IMMUNE DYSFUNCTION
    Abstract: Myeloid-derived suppressor cells (MDSCs) accumulate in cancer patients and tumor-bearing mice and potently suppress T-cell activation. In this study, we investigated whether MDSCs regulate natural killer (NK)-cell function. We discovered that mononuclear Gr-1(+)CD11b(+)F4/80(+) MDSCs isolated from RMA-S tumor-bearing mice do not suppress, but activate NK cells to produce high amounts of IFN-gamma. Gr-1(+)CD11b(+)F4/80(+) MDSCs isolated from tumor-bearing mice, but not myeloid cells from naive mice, expressed the ligand for the activating receptor NKG2D, RAE-1. NK-cell activation by MDSCs depended partially on the interaction of NKG2D on NK cells with RAE-1 on MDSCs. NK cells eliminated Gr-1(+)CD11b(+)F4/80(+) MDSCs in vitro and upon adoptive transfer in vivo. Finally, depletion of Gr-1(+) cells that comprise MDSCs confirmed their protective role against the NK-sensitive RMA-S lymphoma in vivo. Our study reveals that MDSCs do not suppress all aspects of antitumor immune responses and defines a novel, unexpected activating role of MDSCs on NK cells. Thus, our results have great impact on the design of immune therapies against cancer aiming at the manipulation of MDSCs. (Blood. 2008; 112: 4080-4089)
    Type of Publication: Journal article published
    PubMed ID: 18753637
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  • 5
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; IN-VITRO ; BLOOD ; CELL ; Germany ; human ; IN-VIVO ; VITRO ; VIVO ; DISEASE ; DISEASES ; POPULATION ; GENE ; PROTEIN ; DIFFERENTIATION ; MICE ; ACTIVATION ; LIGAND ; CUTTING EDGE ; MACROPHAGES ; MARKER ; CONTRAST ; DENDRITIC CELLS ; T-CELLS ; INJECTION ; IMMUNE-RESPONSES ; STIMULATION ; MOUSE ; PATTERNS ; UP-REGULATION ; FUSION ; MARKERS ; SURFACE ; LIGANDS ; innate immunity ; POPULATIONS ; REVEALS ; PERIPHERAL-BLOOD ; MONOCYTE ; COLONY-STIMULATING FACTOR ; FUSION PROTEIN ; regulation ; USA ; LPS ; macrophage ; immunology ; peripheral blood ; MONOCYTES ; STEADY-STATE ; myeloid cells ; myeloid-derived suppressor cells ; SUPPRESSOR-CELLS ; SEPTIC SHOCK ; TREM-1 ; Toll-like receptor ; myeloid ; MURINE SEPSIS ; Toll-like receptor ligands ; TREM-1 ligand
    Abstract: P〉Triggering receptor expressed on myeloid cells 1 (TREM-1) is an activating receptor involved in inflammatory diseases and septic shock. The TREM-1 ligand(s) (TREM-1L) have not yet been identified. In this study, we performed a detailed analysis of the expression of mouse TREM-1 and its ligand(s). Our results demonstrate that TREM-1 is expressed on bone-marrow-derived dendritic cells (BMDC). On bone-marrow-derived macrophages (BMM) its expression is induced in vitro after stimulation by granulocyte-macrophage colony-stimulating factor, interleukin-3 or by myeloid differentiation primary response gene 88 (MyD88)-dependent Toll-like receptor (TLR) ligands. Under steady-state conditions mouse TREM-1 is detectable on a Gr-1(-) F4/80(+) monocyte subpopulation bearing markers of resident monocytes, but not on Gr-1(+) F4/80(+) inflammatory monocytes. During lipopolysaccharide (LPS)-induced endotoxaemia TREM-1 was also up-regulated on inflammatory Gr-1(+) F4/80(+) cells in vivo. In tumour-bearing mice, TREM-1 was up-regulated on Gr-1(+) F4/80(+) monocytes, which phenotypically and functionally resembled mononuclear myeloid-derived suppressor cells. Using a soluble TREM-1 fusion protein, we demonstrate that after intravenous injection of LPS TREM-1L was induced on Gr-1(+) granulocytes and monocytes but not on other cell populations in peripheral blood. This up-regulation on granulocytes was directly mediated by TLR ligands and required the adapter protein MyD88. In contrast to human, mouse platelets expressed TREM-1L neither under steady-state conditions nor after LPS injection in vivo. Our study reveals differential regulation of TREM-1 expression on mouse monocyte subpopulations and improves our understanding of the biological role of TREM-1 during disease
    Type of Publication: Journal article published
    PubMed ID: 19740375
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  • 6
    Keywords: MEDICINE ; CELLS ; CELL
    Type of Publication: Meeting abstract published
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  • 7
    Keywords: RECEPTOR ; CANCER ; CELLS ; EXPRESSION ; tumor ; CELL ; Germany ; human ; PROTEIN ; MOLECULES ; TUMORS ; LINES ; MICE ; LIGAND ; CUTTING EDGE ; IFN-GAMMA ; MECHANISM ; DENDRITIC CELLS ; mechanisms ; T cells ; T-CELL ; BINDING ; CELL-LINES ; DOWN-REGULATION ; SIGNAL ; HUMANS ; MELANOMA ; DELTA T-CELLS ; NK cells ; NKG2D ; INVOLVEMENT ; CD8(+) ; melanoma cells ; CELL-SURFACE ; cell lines ; INTERFERON-GAMMA ; GENE-MUTATIONS ; CYTOTOXICITY ; STAT1 ; BINDING PROTEIN ; CYTOKINE ; GLIOMA ; therapeutic ; CYTOMEGALOVIRUS UL16 GLYCOPROTEIN ; INTRACELLULAR RETENTION ; natural killer cell ; MHC class I loss ; TUMOR SURVEILLANCE
    Abstract: NKG2D operates as an activating receptor on natural killer (NK) cells and costimulates the effector function of alpha p CD8(+) T cells. Ligands of NKG2D, the MHC class I chain-related (MIC) and UL16 binding protein (ULBP) molecules, are expressed on a variety of human tumors, including melanoma. Recent studies in mice demonstrated that NKG2D mediates tumor immune surveillance, suggesting that antitumor immunity in humans could be enhanced by therapeutic manipulation of NKG2D ligand (NKG2DL) expression. However, signals and mechanisms regulating NKG2DL expression still need to be elucidated. Here, we asked whether the proinflammatory cytokine Interferon-gamma (IFN-gamma) affects NKG2DL expression in melanoma. Cell lines, established from MHC class I-negative and -positive melanoma metastases, predominantly expressed MICA and ULBP2 molecules on their surface. Upon IFN-gamma treatment, expression of MICA, in some cases, also of ULBP2 decreased. Besides melanoma, this observation was made also for glioma cells. Down-regulation of NKG2DL surface expression was dependent on the cytokine dose and the duration of treatment, but was neither due to an intracellular retention of the molecules nor to an increased shedding of ligands from the tumor cell surface. Instead, quantitative RT-PCR revealed a decrease of MICA-specific mRNA levels upon IFN-gamma treatment and siRNA experiments pointed to an involvement of STAT-1 in this process. Importantly, IFN-gamma-treated MHC class I-negative melanoma cells were less susceptible to NKG2D-mediated NK cell cytotoxicity. Our study suggests that IFN-gamma, by down-regulating ligand expression, might facilitate escape of MHC class I-negative melanoma cells from NKG2D-mediated killing by NK cells. (C) 2008 Wiley-Liss. Inc
    Type of Publication: Journal article published
    PubMed ID: 19089914
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