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  • 1
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    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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  • 3
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; CELL ; Germany ; human ; TYROSINE KINASE ; PROTEIN ; RNA ; cell line ; LINES ; TRANSDUCTION ; ACTIVATION ; COMPLEX ; RESPONSES ; COMPLEXES ; CUTTING EDGE ; DENDRITIC CELLS ; CELL-LINES ; PHOSPHORYLATION ; signal transduction ; SIGNAL ; MOUSE ; PATTERNS ; SIGNAL-TRANSDUCTION ; CELL-LINE ; LINE ; B-CELLS ; NATURAL-KILLER-CELLS ; NK cells ; cell lines ; REGULATOR ; NEUTROPHILS ; signaling ; RE ; PRODUCTS ; INTERFERENCE ; RNA INTERFERENCE ; LEADS ; CYTOKINE PRODUCTION ; LEVEL ; SIGNALS ; B-CELL ; immunology ; DAP12 ; AMPLIFIES INFLAMMATION ; PHOSPHOLIPASE C-GAMMA-1
    Abstract: The engagement of triggering receptor expressed on myeloid cells 1 (TREM-1) on macrophages and neutrophils leads to TNF-alpha and IL-8 production and enhances inflammatory responses to microbial products. For signal transduction, TREM-1 couples to the ITAM-containing adapter DNAX activation protein of 12 kDa (DAP12). In general, ITAM-mediated signals lead to cell activation, although DAP12 was recently implicated in inhibitory signaling in mouse macrophages and dendritic cells. To date, signals downstream of the TREM-1 and DAP12 complex in myeloid cells are poorly defined. By analyzing receptor-induced tyrosine phosphorylation patterns, we discovered that the ligation of TREM-1 leads to tyrosine phosphorylation of the non-T cell activation linker (NTAL; also called linker of activation in B cells or LAB) in a myelomonocytic cell line and primary human granulocytes. Using RNA interference to decrease the expression levels of NTAL, we demonstrate that in NTAL knockdown cell lines the phosphorylation of ERK1/2 is enhanced. In addition, low levels of NTAL are correlated with decreased and delayed mobilization of Ca2+ after TREM-1 triggering. Most importantly, we demonstrate that NTAL acts as a negative regulator of TNF-alpha and IL-8 production after stimulation via TREM-1. Our results show that activation signals delivered via DAP12 can be counterbalanced by the adaptor NTAL, identifying NTAL as gatekeeper of TREM-1/DAP12-induced signaling in myeloid cells. The Journal of Immunology, 2007, 178: 1991-1999
    Type of Publication: Journal article published
    PubMed ID: 17277102
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  • 4
    Keywords: RECEPTOR ; CANCER ; CELLS ; EXPRESSION ; SURVIVAL ; tumor ; TUMOR-CELLS ; CELL ; Germany ; IN-VIVO ; MODEL ; MODELS ; THERAPY ; TISSUE ; TUMORS ; ACCUMULATION ; MICE ; TIME ; PATIENT ; LIGAND ; IFN-GAMMA ; prognosis ; DENDRITIC CELLS ; NUMBER ; LIGANDS ; CANCER-PATIENTS ; PROGNOSTIC-SIGNIFICANCE ; STRATEGIES ; IMMUNE-RESPONSE ; REJECTION ; CANCER PATIENTS ; chemokine ; ONCOLOGY ; RE ; CAPACITY ; THERAPIES ; TUMOR TISSUE ; REGULATORY T-CELLS ; LEVEL ; USA ; survival time ; cancer research ; ANTITUMOR RESPONSES ; NATURAL-KILLER-CELL ; ECTOPIC EXPRESSION ; natural killer ; NK-CELLS ; CHEMOKINE FAMILY
    Abstract: Several studies have correlated high numbers of tumor-infiltrating natural killer (NK) cells with a good prognosis for cancer patients. Our study aimed at identifying factors controlling intratumoral NK cell accumulation in s.c. injected NK cell sensitive tumor models and at studying their effect on survival time of recipient mice. We observed that fewer NK cells infiltrated the tumors in IFN-gamma receptor knockout (IFN-gamma R-/-) mice compared with wild-type controls that correlated with decreased survival rate. Exogenous application of lFN-gamma in the tumor augmented levels of ligands of the chemokine receptor CXCR3, increased NK cell accumulation, and prolonged survival. Furthermore, our data show that CD27(high) NK cells, which under steady-state conditions express CXCR3, preferentially accumulated in the tumor tissue. Accordingly, significantly lower numbers of tumor-infiltrating NK cells were detected in CXCR3(-/-) mice, and the capacity of adoptively transferred CXCR3(-/-) NK cells to accumulate in the tumor was severely impaired. Finally, exogenous application of the CXCR3 ligand CXCL10 in the tumor or ectopic expression of CXCL10 by tumor cells increased the numbers of NK cells in the tumors and prolonged NK cell-dependent survival. Our results identify IFN-gamma and the expression of CXCR3 on NK cells as prerequisites for NK cell infiltration into tumors. Exploiting strategies to augment NK cell accumulation in the tumor might lead to the development of effective antitumor therapies. [Cancer Res 2008;68(20):8437-45]
    Type of Publication: Journal article published
    PubMed ID: 18922917
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  • 5
    Keywords: BEER, BETA, CANCER, CANCER IMMUNOSURVEILLANCE, CARCINOGENESIS, CELL, cell lines, CELL-LINES, CELLS,
    Abstract: Using IL-1/IL-IRa knockout BALB/c mice, we showed that 3-methyleholatrene (3-MCA)-induced carcinogenesis is dependent on IL-1 beta-induced inflammatory responses. Patterns of local inflammation and tumorigenicity were similar in wild-type (WT) and IL-1 alpha(-/-) mice, while in IL-1 beta(-/-) mice, tumorigenicity was attenuated and in IL-1Ra(-/-) mice accentuated. 3-MCA-induced fibrosarcoma cell lines from WT mice developed into progressive tumors in WT mice, while surprisingly, lines from IL-1 alpha(-/-) mice formed tumors only in immunocompromized mice. 3-MCA-induced fibrosarcoma cell lines from IL-1 alpha(-/-) mice, compared with lines from WT mice, manifested higher expression levels of "global" surface molecules related to Ag presentation and interactions with immune surveillance cells (MHC class I, B7.1, B7.2, L-selectin, and NKG2D ligands) and were eradicated mainly by CD4(+)-and CD8(+)-dependent T cell responses. Concomitantly, at the injection site of 3-MCA-induced fibrosarcoma cells derived from IL-1 alpha(-/-) mice, a leukocyte infiltrate, subsequently replaced by a scar-like tissue, was observed. Immune aberrations in NK cell maturation, antitumor specific immunity and killing capacity of effector cells were observed in IL-alpha 1(-/-) mice, in contrast to WT mice. Thus, we demonstrate in this study the significance of host-derived IL-1 alpha in cancer immunoediting, by affecting innate and specific immunosurveillance mechanisms. Overall, the results presented in this study, together with our previous studies, attest to differential involvement of IL-1 alpha and IL-1 beta in tumorigenesis; host-derived IL-1 beta mainly controls inflammation, while concomitantly, IL-1 alpha controls immunosurveillance of the arising malignant cells. Elucidation of the involvement of the IL-1 molecules in the malignant process will hopefully lead to the development of novel approaches for chemoprevention and immunotherapy. The Journal of Immunology, 2009, 182: 4874-4881
    Type of Publication: Journal article published
    PubMed ID: 19342666
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  • 6
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; INHIBITOR ; tumor ; TUMOR-CELLS ; carcinoma ; CELL ; Germany ; human ; DISEASE ; PROTEIN ; PROTEINS ; TUMOR-NECROSIS-FACTOR ; ACTIVATION ; LIGAND ; RESPONSES ; INFECTION ; MECHANISM ; mechanisms ; BINDING ; RECOGNITION ; ACID ; antibodies ; antibody ; PARTICLES ; TARGET ; virus ; NECROSIS-FACTOR-ALPHA ; MELANOMA ; LIGANDS ; NATURAL-KILLER-CELLS ; NK cells ; NKG2D ; SIALIC-ACID ; INTERFERON ; melanoma cells ; RECEPTORS ; CYTOTOXICITY ; APOPTOSIS-INDUCING LIGAND ; GAMMA ; MELANOMA-CELLS ; HEPARAN-SULFATE ; Newcastle disease virus ; USA ; macrophage ; ANTITUMOR VACCINATION ; NECROSIS ; paramyxovirus ; virology ; MODIFIED TUMOR-CELLS ; CYTOTOXICITY RECEPTORS ; NATURAL-KILLER-CELL ; NKG2D ligands ; PARTICLE ; CYTOMEGALOVIRUS UL16 GLYCOPROTEIN ; INFECTED CELLS ; INTRACELLULAR RETENTION ; KILLER-CELL ; natural killer cell
    Abstract: The avian paramyxovirus Newcastle disease virus (NDV) selectively replicates in tumor cells and is known to stimulate T-cell-, macrophage-, and NK cell-mediated responses. The mechanisms of NK cell activation by NDV are poorly understood so far. We studied the expression of ligand structures for activating NK cell receptors on NDV-infected tumor cells. Upon infection with the nonlytic NDV strain Ulster and the lytic strain MTH-68/H, human carcinoma and melanoma cells showed enhanced expression of ligands for the natural cytotoxicity receptors NKp44 and NKp46, but not NKp30. Ligands for the activating receptor NKG2D were partially downregulated. Soluble NKp44-Fc and NKp46-Fc, but not NKp30-Fc, chimeric proteins bound specifically to NDV-infected tumor cells and to NDV particle-coated plates. Hemagglutinin-neuraminidase (HN) of the virus serves as a ligand structure for NKp44 and NKp46, as indicated by the blockade of binding to NDV-infected cells and viral particles in the presence of anti-HN antibodies and by binding to cells transfected with HN cDNA. Consistent with the recognition of sialic acid moieties by the viral lectin HN, the binding of NKp44-Fc and NKp46-Fc was lost after desialylation. NKp44- and NKp46-CD3 zeta lacZ-inducible reporter cells were activated by NDV-infected cells. NDV-infected tumor cells stimulated NK cells to produce increased amounts of the effector lymphokines gamma interferon and tumor necrosis factor alpha. Primary NK cells and the NK line NK-92 lysed NDV-infected tumor cells with enhanced efficiency, an effect that was eliminated by the treatment of target cells with the neuraminidase inhibitor Neu5Ac2en. These results suggest that direct activation of NK cells contributes to the antitumor effects of NDV
    Type of Publication: Journal article published
    PubMed ID: 19515783
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  • 7
    Keywords: CANCER ; CELLS ; EXPRESSION ; tumor ; TUMOR-CELLS ; carcinoma ; PATHWAY ; GENE-EXPRESSION ; PROTEIN ; TRANSDUCTION ; ACTIVATION ; cervical cancer ; human papillomavirus ; ADHESION ; HPV16 ; HUMAN-PAPILLOMAVIRUS ; NATURAL-KILLER-CELLS ; NK cells ; UTERINE CERVIX ; NF-kappa B ; IMMUNOLOGICAL SYNAPSE ; ONCOLOGY ; INTERCELLULAR-ADHESION MOLECULE-1 ; CERVICAL KERATINOCYTES ; CONJUGATION ; ICAM-1
    Abstract: NK cell recognition of tumor cells is mediated by a delicate balance of signals received by MHC class I-binding inhibitory NK cell receptors and activating NK cell receptors, which mainly bind to virus-, stress- or tumor-induced ligands. In addition, adhesion molecules such as the intercellular adhesion molecule-1 (ICAM-1) and its receptors, the lymphocyte function-associated antigen-1 (LFA-1) and Mac-1, are crucial for immune synapse formation and NK cell-mediated killing. In this study, we show that expression of the adhesion molecule ICAM-1 was rapidly induced by E6 and -E7 oncoproteins of HPV16, -18, -5 and -8, but not of HPV38 and -6 in primary human keratinocytes after retroviral transduction. ICAM-1 was upregulated in E6E7-expressing keratinocytes both at mRNA and protein levels. The observed ICAM-1 upregulation in HPV16-E6E7-expressing keratinocytes was partially dependent on activation of the NF-kappaB pathway. Importantly, the upregulated ICAM-1 expression in HPV16-E6E7-expressing keratinocytes led to enhanced conjugate formation with NK cells. We previously showed that HPV16-positive cervical carcinomas frequently express low levels of inhibitory NK cell ligands and high levels of activating NK cell ligands. Moreover, levels of the adhesion molecule ICAM-1 are enhanced by HPV16-E6/E7. Therefore, strategies that aim at harnessing NK cells might be beneficial for the treatment of cervical carcinoma.
    Type of Publication: Journal article published
    PubMed ID: 20473930
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  • 8
    Keywords: CD8(+) T-CELLS ; innate immunity ; NATURAL-KILLER-CELLS ; NK cells ; PROGNOSTIC-SIGNIFICANCE ; I INTERFERON ; INTERFERON-ALPHA ; VIRAL-INFECTION ; IFN-alpha ; Newcastle disease virus ; SUPPRESSOR-CELLS ; anti-tumor ; FUNCTIONAL-SIGNIFICANCE ; Hemagglutinin-Neuraminidase
    Abstract: A plasmid encoding the Hemagglutinin-Neuraminidase (HN) protein of Newcastle Disease Virus (pHN) was tested for its capacity to stimulate innate anti-tumor activity in tumor-bearing mice. We observed that application of the pHN plasmid at the ear pinna site (i.e.) of mice induces higher levels of systemic interferon-alpha and reduced tumor growth in the prophylactic mammary carcinoma DA3 tumor model in comparison to application of a control plasmid not encoding the HN protein. Analysis of the tumor microenvironment revealed a significant increase in NK cell infiltration and decrease in infiltration of CD11b(+)Gr-1(high) myeloid cells bearing the myeloid-derived suppressor cell (MDSC) phenotype after vaccination with the pHN DNA compared to a control DNA. Finally, innate immunity and partially type I IFN responses were proved important for the reduction of s.c. RMA-S tumor growth after pHN vaccination, as shown with the use of RAG2(-/-) and RAG2(-/-)IFNAR1(-/-) mice. These data demonstrate that triggering innate immunity by pHN application at the ear pinna of mice modulates the immune cell compartment in the tumor microenvironment and reduces tumor growth. This highlights thus the potential adjuvant activity of the HN gene in tumor therapy.
    Type of Publication: Journal article published
    PubMed ID: 21172381
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  • 9
    Keywords: EXPRESSION ; ANTIGEN ; NK cells ; ADAPTIVE IMMUNITY ; HLA-E ; INNATE
    Type of Publication: Journal article published
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  • 10
    Keywords: EXPRESSION ; IDENTIFICATION ; CANCER-CELLS ; NATURAL-KILLER-CELLS ; HISTONE DEACETYLASE INHIBITORS ; MESSENGER-RNA STABILITY ; SODIUM VALPROATE ; NKG2D ligands ; CYTOTOXICITY RECEPTOR NKP30 ; CHAIN-B
    Abstract: Natural killer (NK) cells are central effector cells during innate immune responses against cancer. Natural cytotoxicity receptors expressed by NK cells such as NKp30 are involved in the recognition of transformed cells. Recently, the novel B7-family member B7-H6, which is expressed on the cell surface of various tumor cells including hematological malignancies, was identified as an activating ligand for NKp30. To investigate expression and regulation of B7-H6 we generated monoclonal antibodies. Our study reveals that B7-H6 surface protein and mRNA expression in various tumor cell lines was downregulated upon treatment with pan- or class I histone deacetylase inhibitors (HDACi) as well as after siRNA-mediated knockdown of the class I histone deacetylases (HDAC) 2 or 3. B7-H6 downregulation was associated with decreased B7-H6 reporter activity and reduced histone acetylation at the B7-H6 promoter. In certain primary lymphoma and hepatocellular carcinoma samples, B7-H6 mRNA levels were elevated and correlated with HDAC3 expression. Finally, downregulation of B7-H6 on tumor cells by HDACi reduced NKp30-dependent effector functions of NK cells. Thus, we identified a novel mechanism that governs B7-H6 expression in tumor cells, which has implications for potential cancer treatments combining immunotherapy with HDACi.
    Type of Publication: Journal article published
    PubMed ID: 23801635
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