Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human immunodeficiency virus (HIV) infection leads to a progressive loss of CD4+ T helper (Th) type 1 cell-mediated immunity that is associated with defective in vitro CD4+ T cell proliferation and abnormal T cell death by apoptosis in response to T cell receptor (TCR) stimulation. Quantification of interleukin (IL)-2, interferon gamma, IL-4, IL-5, and IL-10 secretion by immunoassays, and of interferon gamma, IL-4 and IL-10 messenger RNA expression by competitive reverse transcriptase polymerase chain reaction after in vitro stimulation of the TCR revealed a similar Th1 cytokine profile in T cells from HIV-infected persons and from controls. These data indicated that the loss of CD4+ Th1 cell function in HIV-infected persons is not related to a Th1 to Th2 cytokine switch as previously proposed, but to a process of activation-induced death of CD4+ Th1 cells. Despite the absence of elevated levels of Th2 cytokines, apoptosis of CD4+ T cells, but not of CD8+ T cells, was prevented in vitro by antibodies to IL-10 or IL-4, two Th2 cytokines that downregulate Th1 cell responses, or by the addition of recombinant IL-12, a cytokine that upregulates Th1 functions. TCR-induced apoptosis of T cell hybridomas and preactivated T cells has been shown to involve the CD95 (Fas/Apo-1) molecule. CD4+ and CD8+ T cells from HIV-infected persons expressed high levels of the CD95 molecule, and, in contrast to T cells from controls, were highly sensitive to antibody-mediated CD95 ligation, which induced apoptosis in a percentage of T cells similar to that induced by TCR stimulation. As TCR-induced apoptosis, CD95-mediated apoptosis of CD4+ T cells, but not of CD8+ T cells, was prevented by the addition of recombinant IL-12. Together, these findings suggest that apoptosis of CD4+ T cells from HIV-infected persons involves an abnormal sensitivity to CD95 ligation, and to TCR stimulation in the presence of normal levels of Th2 cytokines. The preventive effect of IL-12 on both mechanisms has potential implications for the design of immunotherapy strategies aimed at the upregulation of CD4+ Th1 cell functions in AIDS.
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PMID:T helper type 1/T helper type 2 cytokines and T cell death: preventive effect of interleukin 12 on activation-induced and CD95 (FAS/APO-1)-mediated apoptosis of CD4+ T cells from human immunodeficiency virus-infected persons. 750 20

The Fas antigen is a transmembrane receptor that can trigger apoptosis in a variety of tumor and hematopoietic cells. Ovarian follicular atresia and luteolysis are thought to occur by apoptosis. Using reverse transcriptase-polymerase chain reaction (RT-PCR) and flow cytometry, we demonstrated that human granulosa/luteal cells express the Fas antigen. An anti-human Fas antigen monoclonal antibody (Fas mAb; clone CH-11), which induces apoptosis in other cell types by binding to the Fas antigen, induced significant cell death (30%) in cultures pretreated with interferon gamma (IFN gamma). This agrees with studies on tumor cell lines showing that IFN gamma enhances cytotoxic effects of Fas mAb. Granulosa/luteal cells exhibited morphological characteristics typical of apoptosis, including membrane blebbing and condensed chromatin. DNA fragmentation into oligonucleosomal units of approximately 180 bp, typical of apoptosis, was detected at elevated levels in Fas mAb-treated cultures via 3' end-labeling and gel electrophoresis. Examination of cultured cells in situ for apoptotic DNA cleavage by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-digoxigenin nick end-labeling (TUNEL) indicated that more apoptotic death occurred in Fas mAb-treated cultures than in control cultures. Effects of hCG-induced luteinization of cultures on Fas mAb-induced cytotoxicity was examined: combined pretreatment with IFN gamma and hCG induced a synergistic increase in Fas mAb-induced cytotoxicity (40%) over that obtained with IFN gamma-pretreatment alone (15%). In summary, granulosa/luteal cells express the Fas antigen and are sensitive to Fas mAb-induced apoptosis. Human CG synergized with IFN gamma to increase Fas mAb-induced death.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Fas antigen-mediated apoptosis in human granulosa/luteal cells. 753 48

Fas is a cell surface protein of the tumor necrosis factor receptor, nerve growth factor receptor, CD40 family, and is involved in the control of lymphocyte apoptosis. A mutation in the Fas gene in MRL/lpr mice results in massive lymphoproliferation (lpr) and accelerated autoimmunity. To further study the nature of this defect, Fas mRNA expression was evaluated by reverse transcriptase polymerase chain reaction as well as by Northern blotting. These studies revealed that the wild-type Fas message was produced at approximately 10-fold lower levels in the lpr compared with the ++ substrain of MRL mice. In addition to the wild-type transcript, lpr mice also synthesized chimeric transcripts containing an insertion of the early retrotransposon (ETn). Molecular cloning and nucleotide sequencing of a Fas-ETn chimeric cDNA suggested that the striking reduction in wild-type Fas mRNA levels and the presence of aberrant transcripts in MRL/lpr mice are most likely explained by the insertion of the ETn retrotransposon into an intron of the Fas gene and induction of alternative splicing involving the 5' ETn long terminal repeat.
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PMID:The defect in Fas mRNA expression in MRL/lpr mice is associated with insertion of the retrotransposon, ETn. 768 33

Fas ligand (FasL, Apo-1L) is a member of the tumor necrosis factor protein family and binding to its receptor (Fas, Apo-1, CD95) triggers cell death through apoptosis. Ligand expression is restricted to cells with known cytolytic activity and found on hematopoietic cells of the T cell and natural killer lineage. Here we provide evidence that B lymphocytes can express FasL. Flow cytometric analysis revealed that FasL is expressed on the surface of B cells upon stimulation with either lipopolysaccharide or phorbol 12-myristate 13-acetate/ionomycin. FasL expression on activated B cells was confirmed by western blot and reverse transcriptase polymerase chain reaction analysis. FasL on B cells is functional since lipopolysaccharide-activated B lymphocytes derived from wild type, but not from gld mutant mice, were able to kill Fas-sensitive target cells. Our data suggest that the Fas system may contribute to the control of B cell homeostasis.
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PMID:Activated B cells express functional Fas ligand. 860 44

Allograft rejection is dependent on T cell activation, which requires both the engagement of the T cell receptor by antigen in the context of the MHC molecules and costimulatory signals delivered by cell surface molecules such as B7-CD28/CTLA4 pathway. CTLA4-Ig is a fusion protein that blocks this pathway and has previously been shown to prolong both allograft and xenograft survival. The current study demonstrates markedly prolonged murine cardiac allograft survival and specific prolongation of secondary skin grafts using a combination of CTLA4-Ig plus donor bone marrow. A role for hematopoietic chimerism in the establishment of CTLA4-Ig-induced transplantation tolerance was investigated using reverse transcriptase polymerase chain reaction analysis of recipient tissues. Expression of donor-specific MHC class II transcripts in both peripheral and lymphoid tissues was demonstrated at greater than 200 days after transplant. To investigate the functional significance of this observation, heart donors, and donor bone marrow were irradiated before transplantation in CTLA4-Ig-treated recipients. A reduction in allograft survival was associated with irradiation of both the donor heart and the bone marrow. These results suggest that there may be a donor-derived radiosensitive element that enhances allograft survival in this model. Reverse transcriptase polymerase chain reaction analysis of allografts of tolerant and control animals at days 5, 8, and 12 after transplantation failed to demonstrate a dramatic difference in the expression of interleukin (IL)-2, IL-4, IL-10, and interferon-gamma message. Cytotoxicity effector transcripts were largely intact in CTLA4-Ig + bone marrow-treated recipients as they showed no decrease in intragraft granzyme, perforin, Fas, or Fas ligand transcripts during thr first 8 days after transplant. These results imply that complex mechanisms may be important for the induction and maintenance of transplantation tolerance in the CTLA4-Ig plus bone marrow murine cardiac allograft model.
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PMID:CTLA4-Ig plus bone marrow induces long-term allograft survival and donor specific unresponsiveness in the murine model. Evidence for hematopoietic chimerism. 862 6

Previous studies have shown that cytokine-dependent eosinophils undergo apoptosis, yet the mechanisms governing this phenomenon remain obscure. Fas antigen is a transmembrane glycoprotein belonging to the tumor necrosis factor receptor family. Cross-linking of Fas antigen in numerous cell types leads to apoptosis. In the present study, we examined the potential role of Fas antigen in the apoptosis of purified blood eosinophils from healthy donors. Cytokine-deprived eosinophils exhibited a time-dependent loss in viability, accompanied by an increase in the number of apoptotic nuclei and in the expression of Fas antigen and its mRNA, as shown by flow cytometry and reverse transcriptase-polymerase chain reaction, respectively. Cross-linking of Fas antigen with an agonistic anti-Fas monoclonal antibody (MoAb) induced a dose- and time-dependent increase in the number of apoptotic nuclei. Furthermore, using an in vitro coculture system, we showed engulfment of anti-Fas MoAb-treated eosinophils by monocyte-derived macrophages. Finally, incubation of eosinophils with the corticosteroid, dexamethasone, induced apoptosis and augmented that triggered by anti-Fas MoAb. Together, these observations suggest that Fas antigen expression and activation is involved in the apoptosis of human eosinophils and may contribute to the resolution of inflammatory allergic reactions in which eosinophil accumulation is a prominent feature.
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PMID:Fas-mediated apoptosis in cultured human eosinophils. 863

Multiple effector cells have been implicated in transplant rejection, including cytotoxic T cells, B cells, macrophages and NK cells. The purpose of this study was to examine the effector pathways which are critical to murine cardiac allograft rejection. RT-PCR (reverse transcriptase-polymerase chain reaction) analysis of syngeneic and allogeneic vascularized heterotopic cardiac grafts at 5, 8 and 12 days following transplantation demonstrate constitutive expression of Fas in both the syngeneic and allogeneic grafts as well as in normal heart. However, FasL, granzyme, and perforin expression were shown to be up-regulated on days 5-12 in the allograft with no expression in syngeneic grafts or in normal hearts. We have recently analyzed the functional significance of T cell cytotoxic pathways and found that neither the Fas nor CD8+ cytotoxic pathways are required for murine cardiac allograft rejection. In light of these results, we investigated the functional significance of other effector cells in the rejection process. B cell deficient C57BL/10-IgHtm1Cgn mice rejected cardiac allografts from normal donors at control rate. Finally, RT-PCR was used to analyze the expression of macrophage effector transcripts in allograft rejection. Transcripts for iNOS (inducible nitric oxide synthase) and TNF alpha (tumor necrosis factor-alpha) were up-regulated on days 5-12 in untreated allografts with undetectable expression in normal heart or syngeneic grafts. These results demonstrate that effective allograft rejection can occur in the absence of B cells and T cell cytotoxicity pathways suggesting that other effector pathways, such as delayed-type hypersensitivity responses by macrophages, may be critical for allograft rejection.
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PMID:Analysis of effector mechanisms in murine cardiac allograft rejection. 876 9

We applied an antibody against an apoptosis mediator, Fas/APO-1/CD95, to HeLa-derived cells that completely lack mitochondrial DNA (mtDNA) or have mutant mtDNAs. The anti-Fas antibody killed the cells completely lacking mtDNA (EB8), at concentrations as low as 1 ng/ml, but not control cells harboring wild-type mtDNA (Ft2-11). TUNEL (terminal deoxynucleotidyl transferase mediated dUTP-biotin nick end-labeling) and analysis of fragmented DNA indicated that the cell death of EB8 was due to apoptosis. The antibody was cytotoxic to other two cell lines harboring mutant mtDNA with a point mutation or a large-scale deletion. RT-PCR (reverse transcriptase-polymerase chain reaction) showed that the mRNA content of the Fas gene was 2 to 19-fold higher in the cells with deficient mtDNA than in the control cells. In addition, the expressed Fas protein was detected by immunohistochemical staining in the cells without mtDNA but not in the control cells. Incubating the cells containing wild-type mtDNA with the respiratory inhibitors rotenone and antimycin A enhanced the content of mRNA of the Fas gene 2 to 4-fold and sensitized cells to the antibody. Thus, defects in mitochondria caused apoptotic cell death by anti-Fas antibody and enhanced Fas gene expression.
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PMID:Expression of the apoptosis-mediator Fas is enhanced by dysfunctional mitochondria. 890 26

Fas/APO-1 (CD95)-mediated apoptosis is one of the major mechanisms of programmed cell death. We have previously shown by reverse transcriptase-polymerase chain reaction that Fas is frequently expressed in malignant gliomas [Tachibana et al. (1995) Cancer Res 55: 5528-5530]. In this study, we assessed Fas expression in astrocytomas using a polyclonal anti-Fas antibody. Immunoreactivity to Fas was detected in 1 out of 9 (11%) low-grade astrocytomas (WHO grade II), 2 of 11 (18%) anaplastic astrocytomas (WHO grade III) and in 13 of 15 (87%) glioblastomas (WHO grade IV). In glioblastomas, Fas expression was almost exclusively observed in glioma cells surrounding foci of necrosis. In these perinecrotic areas, there was also an accumulation of glioma cells undergoing apoptosis, as detected by in situ nick-end labeling. This suggests that Fas-mediated apoptosis may play a role in the pathogenesis of necrosis which constitutes a histological hallmark of glioblastoma multiforme.
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PMID:Preferential expression of Fas/APO1 (CD95) and apoptotic cell death in perinecrotic cells of glioblastoma multiforme. 892 52

Recent evidence has supported the hypothesis that chemotherapeutic drugs and radiation induce an apoptotic pathway that requires the active participation of the cell. One pathway of apoptosis in malignant lymphoid cells is mediated by the Fas antigen. We studied the human myeloma (8226) and T-cell leukemia (CEM) cell lines selected for resistance to the anthracenes, doxorubicin or mitoxantrone, by continuous culture in the presence of either agent. We found that these drug-resistant cell lines were also resistant to Fas-mediated apoptosis in a dose-dependent manner. The degree of resistance to Fas-mediated apoptosis correlated directly with the level of resistance to chemotherapeutic drugs. These observations indicate that, as cancer cell lines develop mechanisms of drug resistance, they may also develop mechanisms of resistance to physiologic signals of apoptosis. Two mechanisms of resistance to Fas-mediated apoptosis were observed in these cell lines. One mechanism was associated with a dose-dependent reduction in the surface expression of Fas antigen. Analysis of RNA by reverse transcriptase-polymerase chain reaction assays showed that the reduction of Fas antigen expression occurred at the level of transcription. A second mechanism of drug resistance showed no decrease of Fas antigen expression; however, the apoptotic response was diminished. In this situation, removal of the chemotherapeutic agent resulted in a partial reversion to chemosensitivity and re-expression of the Fas antigen, but these cell lines did not regain the ability to undergo apoptosis in response to cross-linking by anti-Fas antibody. These findings support the hypothesis that apoptosis mediated by both chemotherapeutic agents and physiologic stimuli may share a common downstream effector. The demonstration that selection for drug resistance in hematopoietic cell lines results in a simultaneous resistance to Fas-mediated apoptosis may have clinical implications in the development of strategies for the treatment of resistant disease. Further analysis of the molecular mechanisms of Fas expression and function will facilitate the design of biological response modifying agents for the treatment of malignancy.
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PMID:Selection for drug resistance results in resistance to Fas-mediated apoptosis. 905 4


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