Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.48 (transcriptase)
 9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Two distinct cytolytic pathways have been characterized: one in which the interaction between the Fas antigen and its ligand results in apoptosis, and another in which the pore forming protein perforin and the serine protease granzyme B contribute to DNA fragmentation and cell death. We investigated intrarenal expression of these molecular executors of cell death in light of the potential participation of cytolytically active cellular elements in the antiallograft repertory. Reverse transcriptase-polymerase chain reaction was used to identify intrarenal expression of Fas antigen, Fas ligand, granzyme B and perforin in eighty human renal allograft biopsies; mRNA display was correlated with the Banff histological diagnosis of renal allografts. Our studies demonstrate that: (1) intrarenal expression of Fas ligand mRNA and of granzyme B mRNA are correlates of acute but not chronic rejection; (2) Fas ligand mRNA is not detectable in allografts in the absence of rejection; (3) intrarenal coexpression of members of each lytic pathway (Fas ligand and Fas, granzyme B, and perforin) and that of both pathways (e.g., Fas ligand and granzyme B) are correlates of acute rejection; and (4) a direct correlation exists between the histological severity of acute rejection and intrarenal coexpression of mRNA encoding Fas ligand, Fas, granzyme B, and perforin. Our studies identify, for the first time, the differential expression of the two major lytic pathways in acute and chronic allograft rejection and suggest that specific therapy directed at the cytotoxic attack molecules might be efficacious in the prevention and/or treatment of acute rejection.
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PMID:Molecular executors of cell death--differential intrarenal expression of Fas ligand, Fas, granzyme B, and perforin during acute and/or chronic rejection of human renal allografts. 899 Mar 77

Corresponding to the expression of Fas in the ovarian oocytes as previously reported (Guo et al., Biochem Biophys Res Commun 1994; 203:1438-1446; Mori et al., JSIR 1995; 9:49-50), the expression of Fas ligand (FasL) in the ovarian follicle was found to be restricted in the area of granulosa cells by the indirect immunofluorescence (IIF) test. Reverse transcriptase/polymerase chain reaction (RT/PCR) technique coupled with Southern blot hybridization analysis showed that the highest level of FasL mRNA was demonstrated in murine ovaries and granulosa cells 1 day after the administration of pregnant mare's serum gonadotropin (PMSG), while the level of FasL mRNA became very weak on the day 5, respectively. The observed gradual decrease in FasL mRNA could not be attributed to a generalized degradation of cellular RNA during atresia, as evidenced by the presence of constitutive expression of elongation factor 1 alpha (EF-1 alpha) mRNA in murine ovaries and granulosa cells treated with PMSG. Furthermore, in situ hybridization analysis with a FasL-specific probe confirmed that FasL was specifically localized in the granulosa cells of most follicles and its expression was regulated by PMSG administration. FasL localized in granulosa cells might possibly play an important role in the formation of the ovarian atretic follicles, most likely depending on PMSG administration.
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PMID:Expression of Fas ligand in murine ovary. 919 98

Fas/APO-1 (CD95) is a cell surface receptor that mediates apoptosis when it reacts with Fas ligand (FasL) or Fas antibody. We previously reported that Fas expression is predominantly induced in perinecrotic glioma cells, suggesting that Fas induction is associated with apoptosis and necrosis formation, a histological hallmark of glioblastomas. In this study, we assessed the expression of FasL in 10 glioblastoma cell lines and in 14 astrocytic brain tumors (three low-grade astrocytomas and 11 glioblastomas). Reverse transcriptase (RT)-PCR revealed that all glioblastoma cell lines and primary astrocytic brain tumors express FasL. Immunohistochemically, FasL was predominantly expressed on the plasma membrane of glioma cells. These results suggest that FasL expression is common in human astrocytic brain tumors and may cause apoptosis of glioma cells if Fas expression is induced.
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PMID:Fas ligand expression in glioblastoma cell lines and primary astrocytic brain tumors. 921 71

Coculture of cytotoxic T cells (STIL-3 C5) derived from L8313 leukemic mice with hematopoietic supportive stromal cells (MS-5) resulted in the detachment of MS-5 cells from the culture dish, whereas helper T cells (STIL-3 DF) did not induce this detachment. The response of bone marrow (BM) adherent cells to the same treatment was similar to that of MS-5 cells. The detached cells were unable to proliferate further, and genomic DNA of these cells showed fragmentation, suggesting that hematopoietic stromal cells died of apoptosis. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis revealed that STIL-3 C5 cells, but not STIL-3 DF cells expressed perforin, granzyme A & B, and Fas ligand. Fas was expressed in MS-5, BM adherent cells, MS-K and NIH/3T3 cells, which do not support hematopoiesis. These data suggest that the aforementioned factors mediate induction of apoptosis in MS-5 cells induced by direct cell-to-cell interaction with STIL-3 C5. This may explain the mechanism responsible for the destruction of the hematopoietic microenvironment by cytotoxic T cells in L8313 leukemia, from which STIL-3 cells are derived; it also suggests that destruction of hematopoietic tissue may be caused by leukemic cytotoxic T cells in some cases of leukemia.
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PMID:Destruction of hematopoietic microenvironment by cytotoxic T cells. 929

Allospecific CTL can function as cellular effectors of solid organ graft rejection; however, the specific mechanisms of cell damage remain undetermined. In this study we examined the role of CD8+ T cells in apoptosis and rejection of small intestinal allografts. ACI rat intestinal grafts transplanted into Lewis rat recipients showed apoptosis of epithelial crypt cells on day 3 posttransplant as determined by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling staining. By day 7 numerous apoptotic crypt cells were detected in allografts, but were rarely observed in FK506-treated allograft recipients, isografts, or native intestine of allograft recipients. To further investigate the mechanism of rejection, recipient rats were depleted of CD8+ cells by treatment with OX-8 mAbs the day before and the day after transplantation of rat small intestinal allografts. Depletion of CD8+ cells from allograft recipients did not alter the tempo or the histologic features of rejection compared with those in the control (IgG-treated) group. Moreover, there was no difference in the number of apoptotic crypt epithelial cells in the grafts of control and CD8-depleted rats. Reverse transcriptase-PCR analyses determined there were similar levels of transcripts for Fas, Fas ligand, perforin, and granzyme B in control and CD8-depleted allograft recipients. By Western blot it was determined that the levels of Fas ligand protein were increased in the CD8-depleted group compared with those in control and FK506-treated allograft recipients. These data suggest that CD8 cells are not required for tissue injury or apoptotic cell death in small intestine allograft rejection.
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PMID:CD8+ cells are not necessary for allograft rejection or the induction of apoptosis in an experimental model of small intestinal transplantation. 955 67

Fas (APO-1/CD95) is a cell surface receptor that mediates apoptosis when it reacts with Fas ligand (FasL) or Fas antibody. In this study, we analyzed Fas and FasL expression in normal esophageal mucosa and esophageal squamous cell carcinomas. Reverse transcriptase-PCR revealed that Fas, soluble Fas, and FasL were expressed in all eight esophageal squamous carcinoma cell lines analyzed. Furthermore, it was demonstrated that FasL expressed in esophageal carcinoma cells is functional because coculture experiments using FasL-expressing TE-15 esophageal carcinoma cells resulted in apoptosis of Jurkat T leukemia cells, which are sensitive to Fas-mediated apoptosis. Immunohistochemistry of Fas and FasL showed that they are constitutively expressed in normal esophageal mucosa, FasL being predominantly in the basal and suprabasal layers, whereas Fas is in more differentiated layers, i.e., rows of polyhedral cells of the intermediate layers and squamous cells forming the outer layers. In 18 of 19 invasive esophageal squamous cell carcinomas, FasL expression was found in >50% of tumor cells. In contrast, most tumors (15 of 19, 79%) either showed no Fas expression or showed expression in <5% of tumor cells. These alterations were already detected in dysplasia and carcinoma in situ. These results suggest that up-regulation of FasL and down-regulation of Fas expression are early and frequent events associated with the evolution of esophageal squamous cell carcinomas.
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PMID:Up-regulation of Fas (APO-1/CD95) ligand and down-regulation of Fas expression in human esophageal cancer. 960 41

Cytokine-driven activation of hepatic stellate cells (HSC) in tissue injury and inflammation is a key pathogenetic event in liver fibrogenesis leading to an expanded pool of matrix producing myofibroblasts (MFB) which represent the transformed counterpart of HSC. We hypothesize that expansion of the pool of MFB might also be accomplished by modulation of apoptosis, which plays an opposite and complementary role to mitosis in the cellular homeostasis. We characterized the susceptibility of HSC in primary culture and of MFB in secondary culture to apoptosis induced by the soluble Fas ligand (sFasL) and related the effects to the expression levels of Fas (APO-1/CD95) and some major proapoptotic and contra-apoptotic protooncogenes. MFB showed a dose-dependent apoptotic reaction upon exposure to sFasL as evidenced by a strong increase of nucleosomal DNA fragments, loss of cellular DNA, positive TUNEL reaction, and annexin staining. The effect was found only if protein synthesis (cycloheximide) or RNA synthesis (actinomycin D) were arrested. HSC maintained for various times in primary culture were completely resistant to sFasL in combination with cycloheximide, but in late primary cultures (day 7 onward) an increasing susceptibility to sFasL-mediated apoptosis was developed. By semiquantitative reverse-transcriptase polymerase chain reaction (RT-PCR) analysis and alkaline phosphatase-anti-alkaline phosphatase staining Fas receptor was identified both in HSC and MFB at comparable expression levels. The expression of the contra-apoptotic protooncogenes bcl-2 and bcl-xl was found to be much stronger in early HSC than in late HSC and MFB as shown by ribonuclease protection assay. The expression of bcl-2 was additionally confirmed by semiquantitative RT-PCR and immunoblotting. Proapoptotic bax was found in comparable quantities at the RNA level in HSC and MFB but at the protein level MFB showed increased bax expression. It is concluded that transformation of HSC to MFB is paralleled by an increasing sensitivity to sFasL-mediated apoptosis, which might be related to a strong decrease of bcl-2 and bcl-xl expression, leading to a preponderance of proapoptotic gene expression in MFB. Modulation of apoptotic susceptibility of transforming HSC could be an important complementary pathway in the pathogenesis of fibrosis.
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PMID:Transformation-dependent susceptibility of rat hepatic stellate cells to apoptosis induced by soluble Fas ligand. 969 16

Fas transduces apoptotic signals upon cross-linking with the Fas ligand (FasL), which is experimentally replaced by agonistic anti-Fas monoclonal antibodies (mAb). Of eight human malignant hematopoietic cell lines (HL-60, KG-1, THP-1, K562, U937, Jurkat, IM-9, RPMI-8226) examined by flow cytometric analysis, all, except K562, were found to be positive for surface Fas antigen. However, despite surface Fas expression, the agonistic anti-Fas mAb (7C11) induced apoptosis in only three of seven Fas-expressing cell lines (KG-1, Jurkat and IM-9). This Fas-resistance did not correlated with high levels of mRNA either for DcR3, a decoy receptor for FasL, or for FAP-1, a Fas-associated phosphatase that can block the apoptotic function of Fas. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis did not show consistent differences in the expression of Bcl-2 and Bax between Fas-sensitive and Fas-resistant cell lines examined. These findings indicated that the presence or absence of mRNA expression of DcR3, FAP-1, Bcl-2 and Bax did not always correlate with relative sensitivity to Fas-mediated apoptosis. Treatment of cells with cycloheximide converted the phenotype of resistant cell lines from Fas-resistant to Fas-sensitive, and enhanced the sensitivity of Fas-sensitive cell lines. These results suggest that the Fas-resistance is dependent on the presence of labile proteins that determine resistance to Fas-mediated apoptosis and the apoptotic machinery is already in place in Fas-resistant cell lines.
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PMID:Fas-mediated apoptosis and expression of related genes in human malignant hematopoietic cells. 1119 Feb 79

The aim of this study was to test the hypothesis that transferrin (Tf) has anti-apoptotic properties and thereby exerts a cytoprotective effect against tissue damage induced by irradiation and other cytotoxic modalities. This hypothesis was tested in several models, including in vitro human short-term marrow cultures, subpopulations of marrow cells, particularly, CD56(+) natural killer cells (and natural killer cell lines), and in vivo radioprotection of murine marrow cells. Reverse transcriptase polymerase chain reaction analysis was used for determination of cytokine mRNA. Preincubation of human marrow with Tf protected cells (except for a CD56(+) subpopulation) against cell death induced by gamma-irradiation, tumor necrosis factor-alpha (TNF-alpha), and agonistic anti-Fas monoclonal antibody. Deglycosylation of Tf abrogated this action of Tf; conversely, Tf-derived glycans (Tf-Gly) (but not glycans isolated from other proteins) mimicked the effects of the intact Tf molecule on apoptosis. Antibodies specific for the Tf receptor (CD71) did not block the effects of Tf or Tf-Gly on apoptosis. Determination of cytokine mRNA in the course of Fas-mediated apoptosis in the presence of Tf or Tf-Gly showed upregulation of mRNA for Fas ligand and TNF-alpha in CD56(+) and downregulation of these transcripts along with upregulation of mRNA for interleukin-10 in CD3(+) marrow cells. Under these conditions, a distinct increase in Fas-associated phosphatase-1 message was observed in CD3(+) cells that were protected by Tf or Tf-Gly against apoptosis. The in vitro data were confirmed in a murine in vivo model in which pretreatment of mice with Tf protected marrow cells against gamma-irradiation-induced cell death. These data suggest a role for Tf and particularly Tf-Gly in the regulation of programmed cell death, apparently via alterations in cytokine expression, and provide a basis for additional studies on the use of Tf in cytoprotective protocols.
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PMID:Pro-apoptotic and anti-apoptotic effects of transferrin and transferrin-derived glycans on hematopoietic cells and lymphocytes. 1130 Nov 88


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