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  • 1
  • 2
    Keywords: CELLS ; ENDOTHELIAL-CELLS ; EXPRESSION ; CELL ; Germany ; human ; PROTEIN ; MOLECULES ; RESPONSES ; INFECTION ; MECHANISM ; renal ; INDUCTION ; ANTIGEN ; CONTRAST ; mechanisms ; MOLECULE ; antibodies ; antibody ; PARTICLES ; virus ; NO ; PATHOGENESIS ; BETA ; E6 ; CLASS-I ; Jun ; REPLICATION ; INTERFERON ; KINETICS ; CYTOKINE ; pathogen ; VIRUS-INFECTION ; PATHOGENS ; HEMORRHAGIC-FEVER ; HIGH-TITER ; HUMAN MXA PROTEIN ; NUCLEOCAPSID PROTEIN ; PULMONARY SYNDROME ; PUUMALA-HANTAVIRUS ; RENAL SYNDROME ; RESPIRATORY EPITHELIAL-CELLS ; TULA VIRUS
    Abstract: Hantaviruses represent important human pathogens and can induce hemorrhagic fever with renal syndrome (HFRS), which is characterized by endothelial dysfunction. Both pathogenic and nonpathogenic hantaviruses replicate without causing any apparent cytopathic effect, suggesting that immunopathological mechanisms play an important role in pathogenesis. We compared the antiviral responses triggered by Hantaan virus (HTNV), a pathogenic hantavirus associated with HFRS, and Tula virus (TULV), a rather nonpathogenic hantavirus, in human umbilical vein endothelial cells (HUVECs). Both HTNV- and TULV-infected cells showed increased levels of molecules involved in antigen presentation. However, TULV-infected HUVECs upregulated HLA class I molecules more rapidly. Interestingly, HTNV clearly induced the production of beta interferon (IFN-beta), whereas expression of this cytokine was barely detectable in the supernatant or in extracts from TULV-infected HUVECs. Nevertheless, the upregulation of HLA class I on both TULV- and HTNV-infected cells could be blocked by neutralizing anti-IFN-beta antibodies. Most strikingly, the antiviral MxA protein, which interferes with hantavirus replication, was already induced 16 h after infection with TULV. In contrast, HTNV-infected HUVECs showed no expression of MxA until 48 h postinfection. In accordance with the kinetics of MxA expression, TULV replicated only inefficiently in HUVECs, whereas HTNV-infected cells produced high titers of virus particles that decreased after 48 h postinfection. Both hantavirus species, however, could replicate equally well in Vero E6 cells, which lack an IFN-induced MxA response. Thus, delayed induction of antiviral MxA in endothelial cells after infection with HTNV could allow viral dissemination and contribute to the pathogenesis leading to HFRS
    Type of Publication: Journal article published
    PubMed ID: 15163707
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  • 3
    Keywords: RECEPTOR ; CELLS ; EXPRESSION ; Germany ; QUANTIFICATION ; CLONING ; PROTEINS ; MONOCLONAL-ANTIBODY ; IFN-GAMMA ; CONTRAST ; FLOW ; antibodies ; antibody ; LYMPHOCYTES ; VIRUS-LIKE PARTICLES ; MONOCLONAL-ANTIBODIES ; glycosylation ; IMMUNITY ; T-LYMPHOCYTES ; ANTIVIRAL ACTIVITY ; INTERFERON ; INTERFERON-GAMMA ; ELISA ; monoclonal antibody ; BOVINE ; equine cytokine ; horse interferon ; IMMUNE INTERFERON ; OVINE
    Abstract: Interferon-gamma (IFN-gamma) is a key cytokine in cell-mediated immunity. To measure IFN-gamma production of equine lymphocytes (eqlFN-gamma), we developed a quantitative ELISA. Monoclonal antibodies (mAb) were produced against bacterially derived eqIFN-gamma. The mAbs recognised recombinant and lymphocyte-derived eqIFN-gamma in ELISA, Western blotting, as well as flow cytometric and microscopic analysis. In contrast to bacterially derived material, mammalian and insect cell-derived eqIFN-gamma was biologically active but could be neutralised by one of the monoclonal antibodies. Unexpectedly, glycosylation seemed to be required for antiviral activity of eqIFN-gamma. (C) 2004 Elsevier B.V. All rights reserved
    Type of Publication: Journal article published
    PubMed ID: 15661336
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  • 4
    Keywords: CELLS ; CELL ; Germany ; human ; INFORMATION ; PROTEIN ; ACTIVATION ; LIGAND ; RESPONSES ; DNA ; MECHANISM ; CONTRAST ; DENDRITIC CELLS ; MEMORY ; STIMULATION ; ACID ; ACIDS ; NUCLEIC-ACID ; NUCLEIC-ACIDS ; B-CELLS ; LIGANDS ; immune response ; IMMUNE-RESPONSE ; specificity ; I INTERFERON ; HUMAN PERIPHERAL-BLOOD ; TOLL-LIKE RECEPTORS ; MONONUCLEAR-CELLS ; SYSTEMIC-LUPUS-ERYTHEMATOSUS ; BODIES ; secretion ; PROTEIN-A ; dendritic cell ; STAPHYLOCOCCUS-AUREUS ; USA ; immunology ; bacterial ; VIRULENCE FACTOR ; IFN-ALPHA PRODUCTION ; IMMUNE-COMPLEXES ; INTERFERON-PRODUCING-CELLS
    Abstract: Type I IFNs represent a major antimicrobial defense mechanism due to their property of enhancing immune responses by priming both innate and adaptive immune cells. Plasmacytoid dendritic cells (pDC) are the major source of type I IFN in the human body and represent innate immune cells involved in first-line defense against invading pathogens. Although pDC activation has been extensively studied upon stimulation with synthetic TLR ligands, viruses, and intracellular bacteria, there is only scarce information on extracellular bacteria. In this study we show that the triggering of human pDC-derived IFN-alpha secretion by Staphylococcus aureus is independent of TLR2 and specific for coagulase-positive staphylococci. Specificity of the pDC response to S. aureus is independent of the bacterial virulence factors protein A and a-toxin but is mediated by Ag-specific IgG and CD32. S. aureus-induced pDC activation can be blocked by inhibitory DNA oligonucleotides and chloroquine, suggesting that engagement of TLR7/9 by bacterial nucleic acids after CD32-mediated uptake of these compounds may play a central role in this process. Altogether, we propose that in marked contrast to nonselective TLR2-dependent activation of most innate immune cells, pDC activation by S. aureus represents an Ag-specific memory response since it requires the presence of class-switched immunoglobulins
    Type of Publication: Journal article published
    PubMed ID: 18768836
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  • 5
    Keywords: ADIPOSE-TISSUE, bacterial, BINDING, BINDING PROTEIN, BLOOD, CREB-BINDING-PROTEIN, CYTOKINE, DEFICIEN
    Abstract: Inflammatory responses represent a hallmark of numerous pathologies including sepsis, bacterial infection, insulin resistance, and malign obesity. Here we describe an unexpected coactivator function for the nuclear receptor interacting protein 140 (RIP140) for nuclear factor kappa B (NF kappa B), a master transcriptional regulator of inflammation in multiple tissues. Previous work has shown that RIP140 suppresses the expression of metabolic gene networks, but we have found that genetic as well as acute deficiency of RIP140 leads to the inhibition of the proinflammatory program in macrophages. The ability of RIP140 to function as a coactivator for cytokine gene promoter activity relies on direct protein-protein interactions with the NF kappa B subunit RelA and histone acetylase cAMP-responsive element binding protein (CREB)-binding protein (CBP). RIP140-depenclent control of proinflammatory gene expression via RelA/CBP may, therefore, represent a molecular rational for the cellular integration of metabolic and inflammatory pathways
    Type of Publication: Journal article published
    PubMed ID: 18469200
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  • 6
    Keywords: CANCER ; carcinoma ; CARCINOGENESIS ; CANCER-PATIENTS ; CANCER PATIENTS ; BIOPSY ; cancer research ; CARCIN
    Abstract: We have investigated interferon-kappa (IFN-kappa) regulation in the context of human papillomavirus (HPV)-induced carcinogenesis using primary human foreskin keratinocytes (HFK), immortalized HFKs encoding individual oncoproteins of HPV16 (E6, E7, and E6/E7), and cervical carcinoma cells. Here, IFN-kappa was suppressed in the presence of E6, whereas its expression was not affected in HFKs or E7-immortalized HFKs. Transcription could be reactivated after DNA demethylation but was decreased again upon drug removal. Partial reactivation could also be accomplished when E6 was knocked down, suggesting a contribution of E6 in IFN-kappa de novo methylation. We identified a single CpG island near the transcriptional start site as being involved in selective IFN-kappa expression. To prove the functional relevance of IFN-kappa in building up an antiviral response, IFN-kappa was ectopically expressed in cervical carcinoma cells where protection against vesicular stomatitis virus-mediated cytolysis could be achieved. Reconstitution of IFN-kappa was accompanied by an increase of p53, MxA, and IFN-regulatory factors, which was reversed by knocking down either IFN-kappa or p53 by small interfering RNA. This suggests the existence of a positive feedback loop between IFN-kappa, p53, and components of IFN signaling pathway to maintain an antiviral state. Our in vitro findings were further corroborated in biopsy samples of cervical cancer patients, in which IFN-kappa was also downregulated when compared with normal donor tissue. This is the first report showing an epigenetic silencing of type I IFN after HPV16 oncogene expression and revealing a novel strategy on how high-risk HPVs can abolish the innate immune response in their genuine host cells.
    Type of Publication: Journal article published
    PubMed ID: 19887612
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  • 7
    Abstract: In the present study we show that malignant human papillomavirus (HPV)-positive cells lost their ability to synthesize endogenous beta interferon (IFN-beta) upon tumor necrosis factor alpha (TNF-alpha) treatment. IFN-beta transcription, however, was reinducible in nonmalignant HPV-positive cells, which was confirmed in functional protection assays against encephalomyocarditis virus or vesicular stomatitis virus infections. Addition of neutralizing antibodies against IFN-beta blocked the antiviral effect, excluding the possibility that other IFN types were involved. Conversely, both malignant and immortalized cells could be protected against viral cytolysis when either IFN-beta, IFN-alpha, or IFN-gamma was added exogenously. This indicates that only the cross talk between TNF-alpha and the IFN-beta pathways, and not IFN-alpha/beta and IFN-gamma signaling in general, is perturbed in cervical carcinoma cells. Notably, full virus protection was restricted exclusively to nonmalignant cells, indicating that the antiviral effect correlates with the growth-inhibitory and virus-suppressive properties of TNF-alpha. The IFN-regulatory factors IRF-1 and p48 (ISGF3gamma) emerged as key regulatory molecules in the differential IFN-beta response, since their transcription was either absent or only inefficiently enhanced in tumorigenic cells upon treatment with TNF-alpha. Inducibility of both genes, however, became reestablished in cervical carcinoma cells, which were complemented to nontumorigenicity after somatic cell hybridization. Complementation was paralleled by the entire reconstitution of cytokine-mediated IFN-beta expression and the ability of TNF-alpha to exert an antiviral state. In contrast, under conditions where tumor suppression was not accomplished upon somatic cell hybridization, neither expression of IRF-1, p48, and IFN-beta nor antiviral activity could be restored.
    Type of Publication: Journal article published
    PubMed ID: 11739693
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  • 8
    Keywords: SYSTEM ; RATS ; cytokines ; INVOLVEMENT ; PHARMACOKINETICS ; BEHAVIOR ; ANIMAL-MODEL ; forced swimming test ; CHRONIC HEPATITIS-C ; Anhedonia ; Dexamethasone suppression test ; Forced swim test ; IMMOBILITY
    Abstract: Interferon (IFN) alpha proteins are proinflammatory cytokines having immunomodulating and antiviral properties. States during which cytokine systems are activated (e.g., during viral infection or during treatment of chronic hepatitis C and various malignancies with IFN alpha, etc.) can be associated with depression-like syndromes or even full-blown depressive episodes. Therefore, the role of IFN alpha and other cytokines in the pathogenesis of depressive disorder ("cytokine hypothesis of depression") has been assessed for many years with contradictory results. We have investigated whether intraperitoneal administration of high doses (up to 600microg/kg body weight) of pegylated, recombinant human IFN alpha 2a in mice induces changes known to be associated with depression using three different readouts: behavior in a model of despair (Porsolt swim test), presence of anhedonia (sucrose preference test), and sensitivity of the hypothalamic-pituitary-adrenal system (dexamethasone suppression test). We also assessed potential IFN-induced changes in gene expression in the liver. In none of the performed experiments, depression-associated effects could be found despite very high serum levels of IFN-induced antiviral activity compared to levels measured in hepatitis C virus (HCV) patients treated routinely with pegylated recombinant human IFN alpha 2a. The lack of such expected effects is probably due to the fact that pegylated human recombinant IFN alpha 2a does not activate the murine class I IFN receptor. Our results do not support the hypothesis that administration of recombinant pegylated human IFN alpha to mice produces a robust model of depression.
    Type of Publication: Journal article published
    PubMed ID: 20580843
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  • 9
    Keywords: EXPRESSION ; PROTEIN ; INFECTION ; CERVICAL-CANCER ; HUMAN KERATINOCYTES ; EPITHELIAL-CELLS ; DEGRADATION ; NECK-CANCER ; AUTOPHAGY ; INFLAMMASOMES
    Abstract: Infections with high-risk human papillomaviruses (HPVs) are causally involved in the development of anogenital cancer. HPVs apparently evade the innate immune response of their host cells by dysregulating immunomodulatory factors such as cytokines and chemokines, thereby creating a microenvironment that favors malignancy. One central key player in the immune surveillance interactome is interleukin-1 beta (IL-1beta) which not only mediates inflammation, but also links innate and adaptive immunity. Because of its pleiotropic physiological effects, IL-1beta production is tightly controlled on transcriptional, post-translational and secretory levels. Here, we describe a novel mechanism how the high-risk HPV16 E6 oncoprotein abrogates IL-1beta processing and secretion in a NALP3 inflammasome-independent manner. We analyzed IL-1beta regulation in immortalized keratinocytes that harbor the HPV16 E6 and/or E7 oncogenes as well as HPV-positive cervical tumor cells. While in primary and in E7-immortalized human keratinocytes the secretion of IL-1beta was highly inducible upon inflammasome activation, E6-positive cells did not respond. Western blot analyses revealed a strong reduction of basal intracellular levels of pro-IL-1beta that was independent of dysregulation of the NALP3 inflammasome, autophagy or lysosomal activity. Instead, we demonstrate that pro-IL-1beta is degraded in a proteasome-dependent manner in E6-positive cells which is mediated via the ubiquitin ligase E6-AP and p53. Conversely, in E6- and E6/E7-immortalized cells pro-IL-1beta levels were restored by siRNA knock-down of E6-AP and simultaneous recovery of functional p53. In the context of HPV-induced carcinogenesis, these data suggest a novel post-translational mechanism of pro-IL-1beta regulation which ultimately inhibits the secretion of IL-1beta in virus-infected keratinocytes. The clinical relevance of our results was further confirmed in HPV-positive tissue samples, where a gradual decrease of IL-1beta towards cervical cancer could be discerned. Hence, attenuation of IL-1beta by the HPV16 E6 oncoprotein in immortalized cells is apparently a crucial step in viral immune evasion and initiation of malignancy.
    Type of Publication: Journal article published
    PubMed ID: 23935506
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  • 10
    Keywords: Germany ; IN-VIVO ; PATHWAY ; SYSTEM ; DISEASE ; MICE ; PATIENT ; ACTIVATION ; DNA ; INDUCTION ; AUTOIMMUNE-DISEASE ; B-CELLS ; Jun ; ANTIBODY-RESPONSES ; IMMUNE-RESPONSE ; CLEARANCE ; INTERFERON-ALPHA ; TOLL-LIKE RECEPTORS ; AUTOANTIBODIES ; CYTOKINE ; DEFICIENCY ; IFN-alpha ; LEVEL ; autoantibody ; immunology ; autoimmune disease ; apoptotic ; systemic ; COMPLEMENT ; apoptotic DNA ; DENDRITIC CELL ACTIVATION ; erythematosus ; FOLLICULAR LOCALIZATION ; MARGINAL ZONE MACROPHAGES ; systemic lupus
    Abstract: Systemic lupus erythematosus (SLE), an autoimmune disease characterized by chronic nephritis, arthritis and dermatitis, and the presence of antinuclear autoantibodies, is associated with complement factor deficiencies in the classical activation pathway. In addition, IFN-alpha seems to be a key cytokine in SLE as an activated IFN-alpha, system is regularly observed in patients with SLE. Here, we demonstrate that in lupus-susceptible, complement C4-deficient mice the lack of complement results in elevated intravascular levels of apoptotic DNA. The apoptotic DNA is targeted to the splenic marginal zone where it accumulates and induces IFN-alpha. As such, we present here a unifying hypothesis for the induction of SLE that incorporates the role of complement deficiency and elevated levels of IFN-alpha
    Type of Publication: Journal article published
    PubMed ID: 17506029
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