CD95 (Fas/Apo-1) is a broadly expressed death receptor involved in a variety of physiological and pathological apoptotic processes. Since its discovery, defects in CD95/CD95L system have been proposed as major pathogenic factors responsible for impaired immunological tolerance to self antigens and autoimmunity. Later, analysis of altered sensitivity to CD95-induced apoptosis ...

Pseudomonas aeruginosa causes severe infections, particularly of the lung, that are life threatening. Here, we show that P. aeruginosa infection induces apoptosis of lung epithelial cells by activation of the endogenous CD95/CD95 ligand system. Deficiency of CD95 or CD95 ligand on epithelial cells prevented apoptosis of lung epithelial cells in ...

Apoptosis in the immune system is a fundamental process regulating lymphocyte maturation, receptor repertoire selection and homeostasis. Thus, death by apoptosis is as essential for the function of lymphocytes as growth and differentiation. This article focuses on death receptor-associated apoptosis and the role of CD95 (Apo-1/Fas)-mediated signalling in T-cell and ...

CD95 (APO-1/Fas) is a member of the tumor necrosis factor receptor family, which can trigger apoptosis in a variety of cell types. However, little is known of the mechanisms underlying cell susceptibility to CD95-mediated apoptosis. Here we show that human T cells that are susceptible to CD95-mediated apoptosis, exhibit a ...

T cell activation is supposed to require two signals via the TCR and a co-stimulatory molecule. However, the signaling cascade of co-stimulatory molecules has remained elusive. Here we provide evidence that CD44, which is constitutively associated with Ick and fyn, supports proliferation as well as apoptosis mainly, if not exclusively, ...

Hepatocytes constitutively express CD95 (also called Fas/APO-1) and are therefore potential targets for CD95-ligand (CD95L)-mediated injury. To study this mechanism of cell death in hepatocytes we developed an in vitro model of liver cell apoptosis using membrane-bound CD95L as the inducing agent. Primary mouse hepatocytes were cocultured with NIH 3T3 ...

The transcription factor nuclear factor kappaB (NFkappaB) is an essential antagonist of apoptosis during liver regeneration and embryonal development of hepatocytes. Several reports have indicated that NFkappaB may also inhibit the programmed cell death induced by cytokines, ionizing radiation, or cytotoxic drugs in some cancer cell lines. Because hepatocellular carcinomas ...

The Fas/Fas ligand (L) system plays an important role in the maintenance of peripheral B cell tolerance and the prevention of misguided T cell help. CD40-derived signals are required to induce Fas expression on virgin B cells and to promote their susceptibility to Fas-mediated apoptosis. In the current study, we ...

BACKGROUND: The death of cardiac cells during ischemia and reperfusion is partially mediated by apoptosis, as seen, eg, in autopsy material of patients after acute myocardial infarction. METHODS AND RESULTS: To study the role of CD95/Fas/Apo1 for induction of postischemic cell death, we used an ischemia/reperfusion model of isolated rat ...

Ribonucleotide reductase (RR) is the rate-limiting enzyme for the de novo synthesis of deoxyribonucleotides. Its activity is significantly increased in tumor cells related to the proliferation rate. Therefore, the enzyme is considered to be an excellent target for cancer chemotherapy. In the present study, we investigated whether the antineoplastic effects ...

Protein or RNA synthesis inhibitors are known to sensitize some resistant cells for death receptor-induced apoptosis. However, the molecular mechanism(s) involved in sensitization have not yet been defined exactly. Here, we report that metabolic inhibitors such as cycloheximide (CHX) or actinomycin D (ActD) sensitize for CD95-induced apoptosis by strongly down-regulating ...

CD95/CD95L interactions are vital to normal lymphoid homeostasis and in the protection against autoimmunity. To directly assess the effects of CD95L on activated B cell survival and Ig responses, purified human peripheral blood B cells, activated in vitro with SAC + rIL2, were incubated with a soluble CD95L fusion protein ...

CD95 (Fas/APO-1) expression and function and Bcl-2 expression, as well as spontaneous apoptosis in vitro, have been shown to be predictive markers for the in vivo response to chemotherapy in acute myeloid leukaemia (AML). To determine the clinical significance of apoptosis-regulating factors in acute lymphoblastic leukaemia (ALL), we investigated cell ...

Expression of CD95 ligand on parenchymal, epithelial, or tumor cells has been suggested to downregulate the immune response and to control lymphocyte activation. Suppression might be mediated by induction of apoptosis or by inhibition of Ca(2+) channels upon CD95 triggering. We, therefore, aimed to employ this model to modify the ...

The cytokine IL-10 exerts potent immunosuppressive and anti-inflammatory effects, although the mechanisms of this action remain largely unknown. In the present study, we investigated the effects of IL-10 in human peripheral blood monocytes. We were able to demonstrate that IL-10 dose- and time-dependently triggers apoptosis in these cells as detected ...

To gain insight into the mechanisms controlling apoptosis of dendritic cells (DC), human monocyte-derived DC were analyzed for their expression of CD95 (Fas/Apo-1) and their response to CD95 ligation. Although DC expressed the CD95 molecule on their membrane, they did not undergo apoptosis on CD95 ligation unless sensitized by cycloheximide. ...

Casper (c-FLIP) associates with FADD and caspase-8 in signaling complexes downstream of death receptors like Fas. We generated Casper-deficient mice and cells and noted a duality in the physiological functions of this molecule. casper-/- embryos do not survive past day 10.5 of embryogenesis and exhibit impaired heart development. This phenotype ...

Growth factor deprivation-induced apoptosis plays an important role in several cellular systems. However, knowledge of the molecular mechanisms involved are restricted to a few murine models or tumor cell lines. Therefore, we aimed studying signaling pathways leading to apoptosis in activated human peripheral T cells after IL-2 withdrawal. Lymphoblasts from ...

Several inducers of cytotoxic stress promote apoptotic cell death, which, at least in some cases, involves the CD95/CD95 ligand (CD95L) pathway. The induction of the CD95/CD95L pathway can be activated by the activator protein-1 (AP-1)-mediated up-regulation of the CD95L promoter, which is responsible for the induction of apoptosis elicited by ...

BACKGROUND: Local radiotherapy induces systemic effects and influences the immune system. Some of these effects can hardly be explained by direct cellular reactions, but might be triggered by humoral factors. MATERIALS AND METHODS: In seminoma patients we measured the influence of radiotherapy on various lymphocyte subsets by FACS-analysis. We analysed ...

The functional recovery of the immune system in HIV-infected persons receiving HAART and the role of adjuvant immune therapy are still matters of intensive investigation. We analysed the effects of HAART combined with cytokines in 22 naive asymptomatic individuals, randomized to receive HAART (n = 6), HAART plus a low ...

Ligation of CD95 on T lymphocytes resulted in the up-regulation of a cell cycle control protein, p21cip-1/WAF-1, an inhibitor of cyclin-dependent kinases. This up-regulation was completely blocked by the cysteine protease inhibitor Z-VAD-fmk (benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone), whereas DEVD-CHO (succinyl-Asp-Glu-Val-Asp-aldehyde), a caspase 3 inhibitor, had no effect. In Faslpr-cg mice, a point mutation ...

Activation of the CD95 death receptor as well as ionizing radiation induces apoptotic cell death in human lymphoma cells. The activation of caspases is a hallmark of apoptosis induction irrespective of the apoptotic trigger. In contrast to death receptor signaling, the exact mechanisms of radiation-induced caspase activation are not well ...

CD95 and CD95-ligand (CD95L) are physiological mediators of apoptosis required for the control of cell numbers in the human immune system. Discoveries in CD95-dependent mechanisms of immune evasion by tumours suggest regulation by oncogene expression. Clonal contraction of lymphocytes by a CD95/CD95L-independent mechanism has been reported and new evidence supports ...

The effect of CD40, CD54/ICAM-1 and CD95 (Fas/APO-1) ligation in murine B lymphomas was investigated. Crosslinking ligation of CD40 induced p53, the p53-regulated CDKI p21Cip1/Waf1, and apoptosis in 3 lymphoma cell lines of a mature phenotype (A20, M12 and TA3), but not in 2 lymphomas of an immature phenotype (WEHI-279 ...

The activation of the death receptors TNF-receptor-1 (TNF-R1) or CD95, respectively, is a hallmark of inflammatory or viral liver disease. The present thesis investigated the regulation of death receptor-triggered apoptosis by glutathione alterations using different murine in vivo models and an in vitro model of CD95-mediated apoptosis. The findings provide ...

Human immunodeficiency virus-type 1 (HIV-1) infection is characterized by increased immune cell apoptosis. Apoptosis can be triggered by signals that arise from within the cell, or by signals that are elicited by binding of extracellular "death ligands" to their "death receptors," most of which belong to the tumor necrosis factor ...

Cross-linking of the B cell antigen receptor (BCR) induces resistance to Fas (APO-1 / CD95)-dependent apoptosis and thereby regulates one mechanism of B cell selection during antigen stimulation. To investigate the molecular mechanism by which BCR signaling regulates the Fas pathway, we examined the expression of constituents of the death-inducing ...

Several malignant cell lines are resistant to CD95-(Apo1/Fas)-mediated apoptosis, even when the CD95 receptor is highly expressed. Sensitivity to CD95-induced apoptosis can be restored using different molecules. In this study, we showed that quercetin, a naturally occurring flavonoid, in association with the agonistic anti-CD95 monoclonal antibody, increases DNA fragmentation and ...

The induction of apoptosis by death receptors serves to regulate immune responses by eliminating unwanted and harmful cells. Mature lymphocytes express FLICE inhibitory proteins (FLIPs) that block death receptor-induced cell death. Here, we show that both B and T cells downregulate c-FLIP upon activation in vitro. Retrovirus-mediated expression of c-FLIP ...

Disorders in negative growth control by CD95 (APO-1/Fas)-mediated apoptosis have been suggested to facilitate immune evasion of neoplastic cells and resistance to anticancer drugs. The present report describes the expression and function of CD95 receptor and ligand in human renal cell carcinomas (RCC) of all major histological types, presenting in ...

BACKGROUND: Radiotherapy is the single most effective therapy for malignant gliomas. Targeting the CD95 apoptotic pathway is a promising experimental approach to these neoplasms. Here, we asked whether irradiation modulates CD95-mediated apoptosis of human malignant glioma cells in vitro. MATERIALS AND METHODS: LN-18, LN-229 and T98G human malignant glioma cell ...

Cytotoxic drugs commonly used in chemotherapy of leukemia and solid tumors have been shown to primarily act by inducing apoptosis in sensitive target cells. Apoptosis may involve activation of death-inducing ligand/receptor systems such as CD95 (APO-1/Fas). Treatment with anticancer drugs such as doxorubicin, methotrexate, cytarabine, etoposide and cisplatin at therapeutic ...

Lymphoproliferative diseases that occur in immunocompromised patients are frequently associated with herpesviruses. These patients often fare poorly after treatment with conventional chemotherapy. We reported previously that patients with AIDS-related Burkitt's lymphoma (BL) responded to parenteral azidothymidine (AZT) and IFN-alpha. We found that EBV-positive lymphoma cells derived from these patients cultured ...

PURPOSE: Ionizing radiation induces apoptosis in human lymphoma cells. However, the participating molecules and their exact order is unknown. Caspases are reported as essential cysteine proteases required for the activation and execution of programmed cell death. The activator caspase-8 is a key component of the CD95/Fas/APO-1 death receptor-triggered apoptosis pathway. ...

Induction of apoptosis is a hallmark of cytostatic drug and radiation-induced cell death in human lymphocytes and lymphoma cells. However, the mechanisms leading to apoptosis are not well understood. We provide evidence that ionizing radiation induces a rapid activation of caspase-8 (FLICE) followed by apoptosis independently of CD95 ligand/receptor interaction. ...

Pattern formation along the anterior-posterior (A/P) axis of the developing Drosophila wing depends on Decapentaplegic (Dpp), a member of the conserved transforming growth factor beta (TGFbeta) family of secreted proteins. Dpp is expressed in a stripe along the A/P compartment boundary of the wing imaginal disc and forms a long-range ...

Modulating signal transduction pathways represents a promising approach for altering the biological behaviour of haemopoietic malignancies. B-cell chronic lymphocytic leukaemia (B-CLL) cells were treated in vitro with CD40-ligand (CD40L) (CD154) or the protein kinase C modulator Bryostatin-1, exploring the effects on: (a) sensitivity to apoptosis induction by chemotherapeutic drugs (fludarabine, ...

CD95 (APO-1/Fas) and CD137 (ILA/4-1BB) are members of the tumour necrosis factor receptor family, and both are involved in induction of apoptosis in lymphocytes. Contrary to the case of CD95, apoptosis by CD137 is caused by cross-linking of the respective ligand rather than the receptor. Nothing is known so far ...

Deficiency of CD95 (Apo-1/Fas)-mediated apoptosis has recently been found in some autoimmune lymphoproliferative disorders due to inherited mutations of the CD95 gene. In this study, impairment of CD95 ligand-mediated killing of lymphocytes and eosinophils in Churg-Strauss Syndrome (CSS), which was a result of variation of CD95 receptor isoform expression, is ...

Ligation of the Fas receptor induces death-inducing signaling complex (DISC) formation, caspase activation, and subsequent apoptotic death of several cell types. Epstein-Barr virus (EBV)-positive group III Burkitt's lymphoma (BL) cell lines have a marked resistance to Fas-mediated apoptosis, although expressing each of the DISC components, Fas/ APO-1-associated death domain protein ...

CD95-induced apoptosis contributes to the maintenance of homeostasis in both B and T lymphocyte-mediated immunity. B cells increase CD95 expression in response to activation signals and become susceptible to CD95-induced apoptosis. Protection from CD95-mediated death signals can be induced in mature B cells by signals delivered through the B cell ...

We have recently identified two different pathways of CD95-mediated apoptosis (Scaffidi, C., Fulda, S., Srinivasan, A., Feng, L., Friesen, C., Tomaselli, K. J., Debatin, K.-M., Krammer, P. H., and Peter, M. E. (1998) EMBO J. 17, 1675-1687). CD95-mediated apoptosis in type I cells is initiated by large amounts of active ...

Tumor-associated antigens that can be recognized by the immune system include the MAGE-family, p53, MUC-1, HER2/neu and p21ras. Despite their expression of these distinct antigens, tumor elimination by the immune system is often inefficient. Postulated mechanisms include insufficient expression of co-stimulatory or adhesion molecules by tumor cells, or defective processing ...

UVB-induced DNA damage is a crucial event in UVB-mediated apoptosis. On the other hand, UVB directly activates death receptors on the cell surface including CD95, implying that UVB-induced apoptosis can be initiated at the cell membrane through death receptor clustering. This study was performed to measure the relative contribution of ...

The CD95 (APO-1/Fas) system can mediate apoptosis in immune cells as well as in tumour cells, where it may contribute to tumour immune-escape. On the other hand, its induction by anticancer drugs may lead to tumour reduction. Interferongamma (IFNgamma) increases the sensitivity of tumour cell lines to anti-CD95 antibody-mediated apoptosis. ...

Apoptosis is now recognized as a central process of development and disease, and it has been proposed as one of the mechanisms that may account for the lymphopenia seen in some diseases. In this study we measured spontaneous apoptosis and CD95 expression on different cell subpopulations from CVID patients, using ...

Dysregulation of CD95/Fas-mediated apoptosis has been implicated as a contributing factor in autoimmune disorders. Animal studies clearly have established a connection between mercury exposure and autoimmune disease in rodents, while case reports have suggested a link between accidental mercury contamination and autoimmune disease in humans. The mechanism(s) for these associations ...

Normal individuals have mature T lymphocytes that are capable of reacting to self-antigens and can be activated by cross-reacting environmental antigens. The mechanism that maintains immune tolerance and prevents these activated autoreactive T cells from causing autoimmune disease is unclear. We have previously hypothesized that activation-induced apoptosis of previously activated ...

Programmed cell death plays an important role in the neuronal degeneration after cerebral ischemia, but the underlying mechanisms are not fully understood. Here we examined, in vivo and in vitro, whether ischemia-induced neuronal death involves death-inducing ligand/receptor systems such as CD95 and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). After reversible ...