Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:A9QXG9 (bcl-2)
 7,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Retrobulbar fibroblasts are a main target of the immune process in Graves' ophthalmopathy (GO) and have been shown to have unique metabolic qualities. The aim of our study was to analyze the immunoregulatory properties of retrobulbar fibroblasts and particularly whether fibroblasts were able to protect T cells from apoptosis. Retrobulbar fibroblasts from patients with GO spontaneously expressed higher concentrations of HLA class I and HLA class II (p<0.05) than control cells, whereas basal CD54 expression was unimpaired. Stimulation with IFN gamma led to a more pronounced increase in HLA class I, class II and CD54 in autoimmune fibroblasts than in control cells (p<0.05). Fibroblasts from both groups had the capacity to prevent apoptosis in preactivated peripheral T cells during coculture. T cell survival was, however, more pronounced after coculture with retrobulbar fibroblasts than with control cells (p<0.05). Prevention of T cell death was associated with a decreased expression of APO-1 on the T cell surface, whereas the bcl-2 expression of the T cells remained unchanged. Our results suggest that the increased expression of immunoregulatory molecules combined with a pronounced capacity of autoimmune fibroblasts to protect infiltrating T cells from apoptosis might at least partly explain the site selectivity as well as the perpetuation of the extrathyroidal manifestation of Graves' disease.
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PMID:Retrobulbar fibroblasts from patients with Graves' ophthalmopathy induce downregulation of APO-1 in T lymphocytes and protect T cells from apoptosis during coculture. 863 16

Mice defective in Fas (CD95 or APO-1) or its ligand (lpr or gld mice) develop age-dependent lymphadenopathy and systemic autoimmune disease. T cells accumulating in the lymph nodes of these mice express reduced levels of Bcl-2 protein and are susceptible to spontaneous and glucocorticoid-induced apoptosis. We backcrossed bcl-2 transgenic mice to lpr and gld mice to homozygosity to determine the effects of Bcl-2 overexpression. T cells in these mice were resistant to spontaneous and glucocorticoid-induced apoptosis in vitro. Moreover, the accumulation of CD4(-)CD8(-) T cells in the lymph nodes and the spleens was augmented, suggesting that a Bcl-2-dependent mechanism regulating the number of T cells residing in the peripheral lymphoid organs in addition to the Fas-mediated pathway exists.
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PMID:Inhibition of apoptosis and augmentation of lymphoproliferation in bcl-2 transgenic Fas/Fas ligand-defective mice. 864 Aug 68

Stimulation of the Fas (APO-1, CD95) receptor, which is present on a variety of cells, usually triggers a process of programmed cell death. Systemic injection of anti-Fas antibody into mice leads to fulminant liver destruction resulting from massive hepatocyte apoptosis, and to rapid death. Hepatocytes bear Fas but do not express Bcl-2, a protein that plays, in a number of conditions, a protective role against apoptosis. We have generated mice whose liver expresses Bcl-2 as the result of bcl-2 transgene placed under the control of the hepatocyte-specific alpha1-anti-trypsin gene promoter, but is otherwise not distinguishable from that of normal mice. These mice display a marked to almost total resistance to liver damage induced by anti-Fas antibody injection. This protective effect of Bcl-2 occurs in the absence of significant variations, in the stimulated livers, in the level of expression of other proteins also involved in resistance or sensitivity to apoptosis, namely Bcl-x, Bax, Bad, Bak, and p53. Mice with protected livers, however, die almost as rapidly as normal mice, which indicates that acute lethality results from stimulation of Fas receptors present on other target organs or cells.
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PMID:A bcl-2 transgene expressed in hepatocytes protects mice from fulminant liver destruction but not from rapid death induced by anti-Fas antibody injection. 864 44

We determined Fas antigen (CD95) expressions on neoplastic cells from various lymphoid malignancies including adult T-cell leukemia/lymphoma (ATL/L) by a flow cytometoric method. ATL/L cells generally expressed Fas antigen, while few Fas-positive cells were detected in the other lymphoid malignancies such as non-Hodgkin lymphomas, acute lymphoblastic leukemias, and chronic lymphocytic leukemias. The function of Fas antigen was considered normal, since anti-Fas monoclonal antibody induced apoptosis of ATL/L cells. However, clinical subtypes of ATL/L did not associate with the degrees of Fas antigen expression. When recent observations by others were also considered, the apoptosis of ATL/L cells seemed to be under a complex control mechanism which includes a Fas/Fas-ligand system, HTLV-I Tax protein, bcl-2 protein and interleukin-2 (IL-2)/IL-2 receptor system. In addition, the regulation of apoptosis by Fas/Fas-ligand system and bcl-2 protein might be different between T-and B-lineage lymphoid malignancies.
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PMID:[Fas antigen (CD95) expressions and apoptosis of neoplastic cells from various lymphoid malignancies including adult T-cell leukemia/lymphoma]. 874

The Fas/Apo-1 molecule is a member of tumor necrosis factor/nerve growth factor (TNF/NGF) receptor family and is able to induce apoptosis in various type of malignant cells, including most of the human leukemia T-cells. We previously demonstrated that the Fas-resistant variants may exist in highly Fas-sensitive human leukemia T-cell lines. The surface expression of Fas antigen was unchanged in the variant cells, suggesting the requirement of the cytoplasmic mechanism to exert apoptosis. In the present study, we examined the changes in cytoplasmic proteins of the Fas-sensitive and Fas-resistant cells after stimulation with anti-Fas antibody, 2D1. In Western blotting analysis, we found that the stimulation of Fas-sensitive cells with 2D1, but not resistant variants, induced a repression of cyclin-dependent kinases (cdks), p34cdc2 and p33cdk2, along with apoptosis. There was no alteration in the expression of bcl-2, HSP70, HSP90, and cyclin proteins examined. This observation seemed specific to Fas-mediated apoptosis, because calcium ionophore A23187 or sodium azide failed to repress the expression of cdks. These results indicate that the specific depletion of cdks, most likely due to proteolysis, may play a role in Fas-mediated apoptosis.
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PMID:Selective depletion of cyclin-dependent kinases is associated with Fas-mediated apoptosis in human leukemia T-cell lines. 878 21

Apoptosis (programmed cell death) is an important regulatory mechanism in hematopoiesis, and is thought to be a principal mechanism of action of cytotoxic chemotherapy. Proteins that modulate apoptosis include bcl-2, which inhibits apoptosis, and Fas (CD95, also known as APO-1), which induces apoptosis in susceptible cells bound by Fas ligand (FasL). To characterize precisely the expression of these apoptosis-regulatory proteins in normal and neoplastic hematopoiesis, the authors have performed multiparameter flow cytometric (FCM) analysis in a series of normal and abnormal marrow specimens. Among normal hematopoietic elements, bcl-2 expression was highest in myeloblasts (29 [+/- 9] x 10(3) molecules of equivalent soluble fluorochrome [MESF]), and lymphocytes (28[+/- 7] x 10(3) MESF). bcl-2 was essentially undetectable in granulocytes and nucleated red blood cells, whereas monocytes and B-cell precursors expressed intermediate levels of bcl-2 (11[+/- 4] x 10(3) and 7[+/- 1] x 10(3) MESF, respectively). Fas expression increased with granulocytic and monocytic differentiation; myeloblasts expressed 8(+/- 2) x 10(3) MESF, whereas granulocytes (15 [+/- 2] x 10(3) MESF) and monocytes (28[+/- 5] x 10(3) MESF) displayed relatively greater intensity of staining for Fas. Among lymphoid cells, Fas expression was heterogeneous. B cells expressed lower intensity Fas staining than both CD4+ and CD8+ T cells. Myeloblasts in 30 cases of myeloid leukemia and myelodysplasia studied for bcl-2 and/or Fas expression manifested variable levels of these molecules (range 9-105 x 10(3) MESF for bcl-2 and 3-33 x 10(3) MESF for Fas). In addition, intraclonal heterogeneity of bcl-2 and Fas expression was seen in certain cases of AML, which correlated with extent of differentiation. Among 28 cases of B-precursor ALL studied for bcl-2 and/or Fas expression, bcl-2 ranged from 22 to 60 x 10(3) MESF (P < .001 versus normal marrow B-cell precursors), and Fas varied between essentially undetectable levels and 6 x 10(3) MESF. In summary, normal marrow subsets display characteristic levels of the apoptosis-regulatory molecules, bcl-2 and Fas. In hematopoietic neoplasms, expression of bcl-2 and Fas varies among cases, and in some instances, within leukemic blast populations. Further study is required to understand the potential significance of this heterogeneous expression of bcl-2 and Fas in hematologic neoplasia.
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PMID:Multiparameter flow-cytometric analysis of bcl-2 and Fas expression in normal and neoplastic hematopoiesis. 881 92

The cell-surface expression and the functional status of the CD95/Fas antigen on primitive hematopoietic progenitors (PHPs) freshly isolated from human fetal liver (FL) were studied. PHPs were phenotypically defined as CD34++ CD38 -/+ cells. The most immature subfractions of PHPs, CD34++CD38- and CD34+2CD38+ FL cells, expressed CD95, whereas the more mature CD34++CD38++ and CD34+CD38++2 FL cells displayed low CD95 expression. Combinations of cytokines, such as kit ligand (KL) + interleukin-3 or KL + granulocyte-macrophage colony-stimulating factor (GM-CSF) upregulated the expression of CD95 on PHPs upon in vitro culture. Tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) further increased the CD95 expression induced by KL+GM-CSF. The hematopoietic potential of sorted CD34++lineage (lin)- CD95+ versus CD34++ lin-CD95-FL cells was compared by colony-forming unit-culture (CFU-C) assays performed in serum-deprived medium. Lin+ cells were composed of erythrocytes, monocytes, T cells, B cells, and natural killer cells. Our results indicated that both CD95- and CD95+ subsets contained pluripotent progenitors, generating myeloid and erythroid progenitors. The functional status of CD95 and the effects of TNF-alpha and IFN-gamma, cytokines known to induce CD95-mediated apoptosis, were analyzed by incubation of PHPs in the presence of anti-CD95 monoclonal antibodies (MoAbs). The effect of anti-CD95 MoAbs was measured by viable cell counting, flow cytometry, and CFU-C assays. A decrease of CFU-C numbers was observed in the presence of anti-CD95 MoAbs and TNF-alpha and/or IFN-gamma. However, whereas growth factor deprivation induced apoptosis of PHPs, cross-linking of CD95 did not lead to apoptosis of PHPs measured by flow cytometry and viable cell counting. The correlation of increased intracytoplasmic levels of bcl-2 with high levels of cell-surface CD34 and the presence of CD95 on fresh FL cells suggests that bcl-2 may be involved in protecting against CD95-mediated apoptosis of FL PHPs.
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PMID:Expression of Fas/CD95 and Bcl-2 by primitive hematopoietic progenitors freshly isolated from human fetal liver. 882 20

The initial injury in primary biliary cirrhosis (PBC) is the destruction of portal bile ducts. Little information is available on apoptosis and cell proliferation in such bile ducts, so we used immunohistochemical techniques to locate molecules related to apoptosis [Fas antigen, Lewis Y antigen (BM1/JIMRO), and bcl-2 protein] and to cell proliferation (proliferating cell nuclear antigen, PCNA) in 21 patients with PBC. In addition, nick-end labelling was done to locate DNA fragmentation. The expression of these molecules in chronic nonsuppurative destructive cholangitis (CNSDC) was examined. Cell death and PCNA expression were both found in portal bile ducts affected by CNSDC in 7 of the 13 CNSDC patients examined. Fas antigen was found on the plasma membrane and rough endoplasmic reticulum of bile-duct cells with CNSDC in the frozen sections of all 6 patients with CNSDC out of the 9 patients inspected, and this antigen was found also in bile-duct cells without CNSDC in 2 of these 9 patients. It was not found in anatomically normal liver (from 2 patients with Gilbert's disease). The Lewis Y antigen was found in bile ducts with CNSDC and in proliferated ductules in all 16 patients examined. No bcl-2 protein was found in any bile-duct or ductule cells, but it was found in the cytoplasm of lymphocytes surrounding or invading CNSDC. DNA fragmentation was found in the nuclei of bile-duct cells with CNSDC by nick-end labelling. Our study indicated that Fas-mediated apoptosis might be involved in CNSDC, but that bcl-2 protein seems to participate less than Fas. Although the Lewis Y antigen was found in many bile ducts, the relationship between the antigen and apoptosis remains unknown because there was no evidence that this antigen mediates apoptosis.
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PMID:Expression of antigens related to apoptosis and cell proliferation in chronic nonsuppurative destructive cholangitis in primary biliary cirrhosis. 891 13

Dendritic cells (DC) are cells of the hematopoletic system specialized in capturing antigens and initiating T cell-mediated immune responses. We show here that human DC generated in vitro by culturing CD34+ cord blood progenitor cells in granulocyte macrophage colony stimulating factor plus tumor necrosis factor-alpha express the Fas antigen (APO-1, CD95) and undergo apoptosis upon triggering of Fas by mAb. However, only a proportion of the cells die in response to Fas ligation, an observation that may be related to the virtual absence of the bcl-2 protein in about half of the cells. Ligation of DC CD40 by culture on CD40L-transfected fibroblastic cells up-regulates the expression of bcl-2 and, concomitantly, renders DC virtually resistant to Fas-induced apoptosis. Parallel experiments with mature, interdigitating dendritic cells (IDC) isolated from tonsils revealed that IDC express Fas but do not enter into apoptosis following Fas ligation, a finding that may be explained by their high levels of bcl-2. Thus, upon encountering antigen-specific T cells, DC become resistant to Fas-induced apoptosis, as a consequence of CD40 ligation and possibly by mechanisms associated to the up-regulation of bcl-2 protein expression.
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PMID:CD40 ligation counteracts Fas-induced apoptosis of human dendritic cells. 908 75

A total of 244 human renal biopsy cases were examined under the following three categories of renal disease: (i) transplanted kidney (TK; 127 cases); (ii) primary glomerular disease (GD; 88 cases); and (iii) others (29 cases). In these cases, the immunohistochemical distribution of apoptosis-related proteins (Fas antigen and bcl-2 protein) was investigated. Despite no detection in normal kidney tissues, Fas antigen was highly expressed in the tubular epithelium, indicating that Fas antigen expression was induced on the tubular epithelium in human renal disease. Furthermore, in TK Fas antigen expression was significantly frequent in acute rejection including acute rejection borderline (9/43 cases) and acute rejection stages I-III (10/28 cases), as compared with that in control cases (no rejection, 1/32 cases). Fragmented DNA stained with in situ nick end-labeling was predominantly detected in the tubular epithelium in 6 of 48 cases (23 with transplanted kidney and 21 with glomerular disease). Characteristic nuclear apoptotic changes were detected in the tubular epithelium by light microscopy. These results indicate that apoptosis takes place mainly in the renal tubular epithelium. The present experimental study revealed that Fas mRNA transcripts were induced in human renal cell line by interferon-gamma. This suggests that in situ induction of Fas antigen in the tubular epithelium is mediated, at least in part, by cytokines in association with inflammatory lymphocytic infiltrates. It was also revealed that anti-Fas monoclonal antibody induced apoptosis of the renal cell line through stimulation with interferon-gamma. Taken together, the results suggest that induced expression of Fas antigen on the tubular epithelium might play an important role in apoptosis under acute renal graft rejection.
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PMID:Fas antigen expression and its relationship with apoptosis in transplanted kidney. 910 14


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