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  • 1
    Keywords: APOPTOSIS ; CELLS ; EXPRESSION ; INHIBITOR ; tumor ; CELL ; Germany ; human ; IN-VIVO ; MODEL ; DEATH ; PROTEIN ; PROTEINS ; ACTIVATION ; COMPLEX ; RESPONSES ; COMPLEXES ; primary ; DENDRITIC CELLS ; T cell ; T cells ; T-CELL ; T-CELLS ; DOWN-REGULATION ; culture ; IMMUNE-RESPONSES ; resistance ; CELL-DEATH ; UP-REGULATION ; immune response ; IMMUNE-RESPONSE ; CASPASE 8 ; FAS-MEDIATED APOPTOSIS ; SIGNALING COMPLEX ; EFFECTOR ; Bcl-2 ; FLICE-INHIBITORY PROTEIN ; CASPASE-8 ACTIVATION ; ACQUIRE
    Abstract: In the early phase of an immune response, T cells are activated and acquire effector functions. Whereas these short term activated T cells are resistant to CD95-mediated apoptosis, activated T cells in prolonged culture are readily sensitive, leading to activation-induced cell death and termination of the immune response. The translation inhibitor, cycloheximide, partially overcomes the apoptosis resistance of short term activated primary human T cells. Using this model we show in this study that sensitization of T cells to apoptosis occurs upstream of mitochondria. Neither death-inducing signaling complex formation nor expression of Bcl-2 proteins is altered in sensitized T cells. Although the caspase-8 inhibitor c-FLIPlong was only slightly down-regulated in sensitized T cells, c-FLIPshort became almost undetectable. This correlated with caspase-8 activation and apoptosis. These data suggest that c-FLIPshort, rather than c-FLIPlong, confers resistance of T cells to CD95-mediated apoptosis in the context of immune responses
    Type of Publication: Journal article published
    PubMed ID: 14764686
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  • 2
    Keywords: APOPTOSIS ; CELLS ; GROWTH ; IN-VITRO ; tumor ; BLOOD ; CELL ; Germany ; human ; IN-VIVO ; tumor growth ; VITRO ; GENE-EXPRESSION ; ACTIVATION ; MECHANISM ; mechanisms ; T cell ; T cells ; T-CELL ; T-CELLS ; NO ; MEMBRANE ; leukemia ; LYMPHOCYTES ; T-LYMPHOCYTES ; T lymphocyte ; ENDOPLASMIC-RETICULUM ; ANTICANCER DRUGS ; T lymphocytes ; signaling ; RE ; XENOGRAFTS ; TUMOR-GROWTH ; HYDROGEN-PEROXIDE ; USA ; HEPATOCELLULAR-CARCINOMA CELLS ; MEDICINE ; MITOCHONDRIAL PERMEABILITY TRANSITION ; PHOSPHOLIPASE C-GAMMA-1 ; CA2+ MOBILIZATION ; CYCLOPHILIN-D ; SCUTELLARIA-BAICALENSIS GEORGI
    Abstract: Herbs have successfully been used in traditional Chinese medicine for centuries. However, their curative mechanisms remain largely unknown. In this study, we show that Wogonin, derived from the traditional Chinese medicine Huang-Qin (Scutellaria baicalensis Georgi), induces apoptosis in malignant T cells in vitro and suppresses growth of human T-cell leukemia xenografts in vivo. Importantly, Wogonin shows almost no toxicity on T lymphocytes from healthy donors. Wogonin induces prolonged activation of PLC gamma 1 via H2O2 signaling in malignant T cells, which leads to sustained elevation of cytosolic Ca2+ in malignant but not normal T cells. Subsequently, a Ca2+ overload leads to disruption of the mitochondrial membrane. The selective effect of Wogonin is due to its differential regulation of the redox status of malignant versus normal T cells. In addition, we show that the L-type voltage-dependent Ca2+ channels are involved in the intracellular Ca2+ mobilization in T cells. Furthermore, we show that malignant T cells possess elevated amounts of voltage-dependent Ca2+ channels compared with normal T cells, which further enhance the cytotoxicity of Wogonin for malignant T cells. Taken together, our data show a therapeutic potential of Wogonin for the treatment of hematologic malignancies
    Type of Publication: Journal article published
    PubMed ID: 18070986
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  • 3
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; IN-VIVO ; SYSTEM ; DEATH ; NF-KAPPA-B ; TUMOR-NECROSIS-FACTOR ; mechanisms ; T-CELLS ; MEMORY ; CYTOCHROME-C ; IMMUNE-RESPONSE ; SIGNALING COMPLEX DISC ; DOMAIN-CONTAINING PROTEIN ; DEATH RECEPTORS ; FAMILY MEMBER BIM ; FAS-MEDIATED APOPTOSIS ; INTERLEUKIN-2 RECEPTOR-BETA ; PHENOTYPE CD8(+) CELLS
    Abstract: Apoptosis of activated peripheral T cells during the termination phase of an immune response is critical to maintain T-cell homeostasis. Activated T cells can be removed by two mechanisms: activation-induced cell death (AICD) and death by neglect. AICD is triggered by death receptors, whereas death by neglect is induced by cytokine withdrawal. CD95 (APO-1/Fas) belongs to the subfamily of death receptors and plays a major role in AICD. In this review, we focus on the molecular mechanisms of AICD, in particular those involving the CD95 system. Moreover, we discuss the relative contribution of AICD and death by neglect to terminate a T-cell immune response. In order to become fully activated, T cells require a second signal provided by antigen-presenting cells. We discuss how these costimulatory signals counteract pro-apoptotic signals and, finally, which signals might protect T cells from death to generate a pool of memory T cells
    Type of Publication: Journal article published
    PubMed ID: 12752671
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  • 4
    Keywords: APOPTOSIS ; CANCER ; CELLS ; TUMOR-CELLS ; carcinoma ; CELL ; Germany ; human ; IN-VIVO ; HEPATOCELLULAR-CARCINOMA ; PROTEIN ; RNA ; DRUG ; cell line ; LINES ; MICE ; NF-KAPPA-B ; ACTIVATION ; COMPLEX ; LIGAND ; COMPLEXES ; MECHANISM ; FAMILY ; tumour ; mechanisms ; SUFFICIENT ; CELL-LINES ; MEMBER ; MEMBERS ; treatment ; 5-FLUOROURACIL ; ANTITUMOR-ACTIVITY ; hepatocellular carcinoma ; resistance ; CARCINOMA CELLS ; CELL-LINE ; LINE ; CARCINOMA-CELLS ; RECRUITMENT ; sensitivity ; side effects ; CYTOTOXIC LIGAND TRAIL ; TRAIL ; CASPASE 8 ; DISC ; SIGNALING COMPLEX ; TRAIL-INDUCED APOPTOSIS ; APOPTOSIS-INDUCING LIGAND ; FLICE-INHIBITORY PROTEIN ; INTRACELLULAR REGULATION ; POTENT ; HUMAN CANCER ; CASPASE-8 ; CD95-MEDIATED APOPTOSIS ; cFLIP siRNA death receptor ; death-inducing signalling complex DISC ; DECOY RECEPTORS ; drug sensitivity ; POTENTIAL MECHANISM ; TUMORICIDAL ACTIVITY
    Abstract: Tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) exhibits potent antitumour activity upon systemic administration in mice without showing the deleterious side effects observed with other apoptosis-inducing members of the TNF family such as TNF and CD95L. TRAIL may, thus, have great potential in the treatment of human cancer. However, about 60% of tumour cell lines are not sensitive to TRAIL. To evaluate the mechanisms of tumour resistance to TRAIL, we investigated hepatocellular carcinoma (HCC) cell lines that exhibit differential sensitivity to TRAIL. Pretreatment with chemotherapeutic drugs, for example, 5-fluorouracil (5-FU), rendered the TRAIL-resistant HCC cell lines sensitive to TRAIL-induced apoptosis. Analysis of the TRAIL death-inducing signalling complex (DISC) revealed upregulation of TRAIL-R2. Caspase-8 recruitment to and its activation at the DISC were substantially increased after 5-FU sensitisation, while FADD recruitment remained essentially unchanged. 5-FU pretreatment downregulated cellular FLICE-inhibitory protein (cFLIP) and specific cFLIP downregulation by small interfering RNA was sufficient to sensitise TRAIL-resistant HCC cell lines for TRAIL-induced apoptosis. Thus, a potential mechanism for TRAIL sensitisation by 5-FU is the increased effectiveness of caspase-8 recruitment to and activation at the DISC facilitated by the downregulation of cFLIP and the consequent shift in the ratio of caspase-8 to cFLIP at the DISC
    Type of Publication: Journal article published
    PubMed ID: 15105837
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  • 5
    Keywords: APOPTOSIS ; CELLS ; EXPRESSION ; GROWTH ; GROWTH-FACTOR ; INHIBITOR ; SURVIVAL ; CELL ; Germany ; human ; KINASE ; PATHWAY ; PATHWAYS ; DISEASE ; liver ; PROTEIN ; PROTEINS ; transcription ; TRANSDUCTION ; ACTIVATION ; FAMILY ; primary ; INDUCTION ; hepatocytes ; ACTIVATED PROTEIN-KINASE ; MEMBER ; SIGNAL ; CLEAVAGE ; CELL-SURVIVAL ; DAMAGE ; KAPPA-B ; RAT HEPATOCYTES ; CASPASE 8 ; Bcl-2 ; HUMAN HEPATOCYTES ; CD95 ; PHOSPHOINOSITIDE 3-KINASE ; MEDIATED APOPTOSIS ; SIGNAL TRANSDUCER ; ACID-INDUCED APOPTOSIS ; ACUTE LIVER-INJURY ; FULMINANT HEPATIC-FAILURE ; MITOCHONDRIAL RELEASE
    Abstract: CD95 (APO-1/Fas)-mediated apoptosis of hepatocytes plays a central role in the pathophysiology of various human liver diseases. Hepatocyte growth factor (HGF) was shown to exert antiapoptotic functions in rodent hepatocytes. We previously showed that primary human hepatocytes (PHH) are a valuable toot for the investigation of apoptotic processes in liver cells. In this study, we analyzed the influence of HGF on CD95-mediated apoptosis of PHH and its molecular determinants. HGF significantly inhibited CD95-mediated apoptosis of PHH as well as cleavage of caspase-8 and poly (ADP-ribose)polymerase. HGF transcriptionally induced the expression of the anti-apoptotic Bcl-2 family member myeloid cell leukemia-1 (Mcl-1). In contrary, HGF did not alter the expression levels of Bcl-2 or Bcl-(XL). HGF activated survival pathways such as the phosphatidylinositol-3 kinase (PI3K)/Akt pathway, the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase/ERK and the signal transducer and activator of transcription 3 (STAT3) pathway. Notably, HGF triggered serine(727)-but not tyrosine(705)-phosphorylation of STAT3. Pretreatment of PHH with the PI3K inhibitor LY294002 as well as adenoviral transduction of dominant negative Akt1 prevented HGF-mediated Mcl-1 induction and reversed the antiapoptotic effects of HGF. In conclusion, HGF confers survival of PHH by activation of the PI3K/Akt pathway. PI3K/Akt activation by HGF results in the induction of antiapoptotic proteins such as Mcl-1. Thus, application of HGF may be a therapeutic approach to prevent CD95-mediated hepatocellular damage in human liver diseases
    Type of Publication: Journal article published
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  • 6
    Keywords: APOPTOSIS ; CANCER ; CELLS ; IN-VITRO ; INHIBITOR ; tumor ; TUMOR-CELLS ; AGENTS ; BLOOD ; CELL ; COMBINATION ; Germany ; IN-VIVO ; THERAPY ; TOXICITY ; VITRO ; VIVO ; GENE-EXPRESSION ; PROTEIN ; transcription ; NF-KAPPA-B ; TUMOR-NECROSIS-FACTOR ; NITRIC-OXIDE ; TRANSCRIPTION FACTOR ; T cell ; T cells ; T-CELL ; T-CELLS ; treatment ; ALPHA ; TRANSCRIPTION FACTORS ; leukemia ; CANCER-PATIENTS ; OXIDATIVE STRESS ; PERIPHERAL-BLOOD ; TUMOR CELLS ; TRAIL ; TNF-ALPHA ; TRAIL-INDUCED APOPTOSIS ; LEUKEMIA-CELLS ; INHIBITORS ; MALIGNANT-CELLS ; PROGRAM ; RE ; INCREASE ; TUMOR-CELL ; RESISTANT ; CANCER-TREATMENT ; in vivo ; peripheral blood ; viability ; PROSTAGLANDIN E-2 PRODUCTION ; SCUTELLARIAE-RADIX ; SKIN INFLAMMATION
    Abstract: TNF alpha has previously been used in anticancer therapy. However, the therapeutic application of TNF alpha was largely limited due to its general toxicity and the fact that it activates the NF-kappa B-family transcription factors, which are proinflammatory and antiapoptotic. To overcome this problem in vitro, specific NF-kappa B inhibitors or transcription or protein synthesis inhibitors such as actinomycin D and cycloheximide are usually used in combination to increase TNF alpha killing of tumor cells. However, these agents also cause harmful side effects in vivo. We show here that wogonin, derived from the popular Chinese herb Huang-Qin, attenuates NF-kappa B activity by shifting TNF alpha-induced free radical (.) O-2(-) to a more reduced nonradical product, H2O2, and thereby sensitizes TNF alpha-resistant leukemia cells to TNF alpha-induced apoptosis. Importantly, wogonin does not affect the viability of normal peripheral blood T cells. Wogonin also sensitizes TRAIL-induced apoptosis. Our data suggest a potential use of wogonin as a TNF alpha, or TRAIL adjuvant for cancer treatment. Our data also demonstrate how a herbal compound enhances killing of tumor cells with reduced side effects compared with other treatments
    Type of Publication: Journal article published
    PubMed ID: 16931628
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  • 7
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; EXPRESSION ; IN-VITRO ; SURVIVAL ; tumor ; Germany ; IN-VIVO ; INHIBITION ; PATHWAY ; PATHWAYS ; VITRO ; DEATH ; GENE ; MICE ; TRANSDUCTION ; COMPLEX ; COMPLEXES ; MECHANISM ; T-CELL ; T-CELLS ; BINDING ; signal transduction ; CD95 ligand ; CELL-DEATH ; PROMOTER ; MUTATION ; SIGNAL-TRANSDUCTION ; inactivation ; FACTOR-KAPPA-B ; glucocorticoid receptor ; GLUCOCORTICOID-RECEPTOR ; REPRESSION ; CROSS-TALK ; CD95 ; signaling ; molecular ; PROGRAM ; RE ; PH ; regulation ; RHEUMATOID-ARTHRITIS ; INFLAMMATORY RESPONSES ; cell death ; ABILITY ; APOPTOTIC CELLS ; FAS LIGAND ; NEGATIVE REGULATION ; THYMOCYTE DEVELOPMENT
    Abstract: Glucocorticoids (GCs) play an important role in the regulation of peripheral T-cell survival. Their molecular mechanism of action and the question of whether they have the ability to inhibit apoptosis in vivo, however, are not fully elucidated. Signal transduction through the glucocorticoid receptor (GR) is complex and involves different pathways. Therefore, we used mice with T-cell-specific inactivation of the GR as well as mice with a function-selective mutation in the GR to determine the signaling mechanism. Evidence is presented for a functional role of direct binding of the GR to 2 negative glucocorticoid regulatory elements (nGREs) in the CD95 (APO-1/Fas) ligand (L) promoter. Binding of GRs to these nGREs reduces activation-induced CD95L expression in T cells. These in vitro results are fully supported by data obtained in vivo. Administration of GCs to mice leads to inhibition of activation-induced cell death (AICD). Thus, GC-mediated inhibition of CD95L expression of activated T cells might contribute to the anti-inflammatory function of steroid drugs
    Type of Publication: Journal article published
    PubMed ID: 15802531
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  • 8
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; EXPRESSION ; IN-VITRO ; CELL ; human ; MODEL ; VITRO ; VIVO ; GENERATION ; SYSTEM ; DEATH ; ACTIVATION ; MECHANISM ; T cell ; T cell activation ; T cells ; T-CELL ; T-CELLS ; MEMORY ; AMPLIFICATION ; resistance ; CELL-DEATH ; UP-REGULATION ; MITOCHONDRIA ; PHENOTYPE ; IMMUNE-RESPONSE ; ELIMINATION ; FLICE ; SIGNALING COMPLEX ; EFFECTOR ; Bcl-2 ; C-FLIPSHORT ; CD95 ; signaling ; FAS ; SWITZERLAND ; LEVEL ; PHASE ; RESISTANT ; EXPANSION ; CD4-T-CELL HELP ; CD8-T-CELL MEMORY ; memory cells ; RECEPTOR SIGNALS
    Abstract: An adaptive immune response implies expansion of activated T cells and subsequent elimination to maintain homeostasis in a process called activation-induced cell death. Some cells, however, differentiate into memory cells and ensure a strong secondary immune response. To analyze the apoptosis phenotype of memory T cells on a cellular and molecular level, we have established an in vitro model of T cell activation and generation of cells phenotypically and functionally similar to memory cells. These long-term cultured T cells show a CD95-resistant phenotype, although they are still sensitive towards TCR/CD3-mediated apoptosis. Biochemical analysis revealed that these cells shift from CD95 type I (direct signaling from the receptor) during the effector phase to CD95 type II cells (dependent on the mitochondrial amplification loop). Moreover, their mitochondria are protected, probably due to high expression levels of Bcl-x(L) and Bcl-2. Thus, our data suggest a mechanism how memory T cells acquire resistance towards bystander cell death via the CD95 system
    Type of Publication: Journal article published
    PubMed ID: 17048269
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  • 9
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; GROWTH ; GROWTH-FACTOR ; IN-VITRO ; CELL ; Germany ; IN-VIVO ; INHIBITION ; MODEL ; MODELS ; PATHWAY ; PATHWAYS ; VITRO ; VIVO ; DEATH ; liver ; DRUG ; MICE ; TUMOR-NECROSIS-FACTOR ; ACTIVATION ; COMPLEX ; COMPLEXES ; INFECTION ; MECHANISM ; LIVER-TRANSPLANTATION ; TRANSPLANTATION ; RAT ; T-CELLS ; LYMPHOMA ; PROSTATE-CANCER ; DAMAGE ; SIGNALING PATHWAY ; SIGNALING PATHWAYS ; HEPATOMA ; Jun ; INFECTIONS ; RECEPTORS ; DEATH RECEPTORS ; DISC ; FLICE ; SIGNALING COMPLEX ; LYMPHOMA-CELLS ; CD95 ; signaling ; DISORDERS ; PROGRAM ; CASPASE-8 ; PH ; MEDIATED APOPTOSIS
    Abstract: Suramin is a polysulfonated derivative of urea and has been widely used both to treat infections and as a chemotherapeutic drug. Suramin has been shown to inhibit growth factor signaling pathways; however, its effect on apoptosis is unknown. Here we show that suramin inhibits apoptosis induced through death receptors in hepatoma and lymphoma cells. It also inhibits the proapoptotic effect of chemotherapeutic drugs. The antiapoptotic mechanism is specific to cell type and is caused by reduced activation, but not altered composition, of the death-inducing signaling complex (DISC), and by inhibition of the initiator caspases 8, 9 and 10. Suramin also shows similar effects in in vivo models: apoptotic liver damage induced by CD95 stimulation and endotoxic shock mediated by tumor-necrosis factor (TNF) are inhibited in mice, but necrotic liver damage is not inhibited in a rat model of liver transplantation. Thus, the antiapoptotic property of suramin in the liver may be therapeutically exploited
    Type of Publication: Journal article published
    PubMed ID: 15146177
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  • 10
    Keywords: RECEPTOR ; APOPTOSIS ; CELLS ; GROWTH ; GROWTH-FACTOR ; tumor ; CELL ; SYSTEM ; SYSTEMS ; DEATH ; DISEASE ; DISEASES ; DISTINCT ; COMPONENTS ; MECHANISM ; IMPACT ; ANTIGEN ; ANTIGENS ; AUTOIMMUNE-DISEASE ; mechanisms ; T cell ; T cells ; T-CELL ; T-CELLS ; CELL-DEATH ; IMMUNE-RESPONSE ; RECEPTORS ; MULTIPLE-SCLEROSIS ; CD95 ; signaling ; CYTOKINE ; DISORDERS ; MOLECULAR-MECHANISM ; TUMORIGENESIS ; FAS ; AUTOIMMUNE-DISEASES ; IMMUNE-SYSTEM ; AICD ; death receptor ; multiple sclerosis ; function ; autoimmune disease ; NECROSIS
    Abstract: Death receptors belong to the TNF (tumor necrosis factor)/NGF (nerve growth factor) receptor superfamily. Signaling via death receptors plays a distinct role, e.g. in the immune system, where it contributes to regulation of the adaptive immune response in various ways, most notably by triggering activation-induced cell death (AICD) of T cells. Thus, dysregulation of death receptor signaling, either allowing too much or too little apoptosis, can lead to autoimmune disorders and also impacts on tumorigenesis or other diseases. In this chapter we address components, molecular mechanisms and regulation of death receptor signaling with particular focus on CD95 (APO-1, Fas). We discuss the role of death receptor-mediated AICD in regulation of the adaptive immune response against foreign and self antigens in comparison to cytokine deprivation-mediated death by neglect. Finally, the contribution of dysregulated death receptor/ligand systems to autoimmune diseases such as diabetes, multiple sclerosis and Hashimoto's thyroiditis is discussed.
    Type of Publication: Journal article published
    PubMed ID: 16394652
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