Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P08758 (annexin V)
 9,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apoptosis of neutrophils limits their pro-inflammatory potential. We tested the ability of fresh and cultured whole blood neutrophils to undergo spontaneous apoptosis and expression of p53, Fas/Apo-1, bcl-2 protein in the cells using flow cytometry. Neutrophil apoptosis was estimated using Annexin V and propidium iodide binding and verified under light microscopy. The percentage of early and late apoptotic neutrophils in the blood samples increased significantly after 20 h culture from 12.3 +/- 14.2% and 4.3 +/- 4.2% to 39.5 +/- 14% and 15.3 +/- 9.6%, respectively. The majority of late apoptotic neutrophils had altered morphology in FSC/SSC dot plot compared to alive or early apoptotic neutrophils. Cultured neutrophils presented markedly lower expression of bcl-2 protein compared to fresh blood cells: 211 +/- 321 median of fluorescence intensity (MFI) and 787 +/- 1152 MFI, respectively. The increased percentage of late apoptotic cells after culture paralleled the increase in the Fas/Apo-1 expression and negatively correlated with bcl-2 expression. We noted intracellular expression of p53 protein in neutrophils, although the expression did not correlate neither to the percentage of the apoptotic neutrophils, nor to the Fas/Apo-1 or bcl-2 expression. Our results suggested that neutrophil apoptosis is gene regulated, moreover, we present a possibility to assess the neutrophil apoptosis and cellular expression of the proteins of apoptosis related genes in whole blood samples.
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PMID:Spontaneous apoptosis of neutrophils in whole blood and its relation to apoptosis gene proteins. 1111 49

Disturbances in apoptosis or in the clearance of apoptotic material might result in increased presentation of autoantigens which could be relevant to the pathogenesis of SLE. Data concerning defects in apoptosis in SLE are conflicting. To determine whether intrinsic defects in apoptosis induction occur in SLE irrespective of disease activity, we examined anti-CD3 and anti-Fas-induced apoptosis in vitro in SLE patients with inactive disease. Isolated peripheral blood lymphocytes (PBL) from 13 SLE patients and 14 healthy controls were incubated with anti-CD3, and, subsequently, after up-regulation of membrane Fas following anti-CD3 incubation, with anti-Fas. Expression of Fas and levels of apoptosis as detected by annexin V and propidium iodide staining were assessed by flow cytometry before and after the respective incubations. Fas expression on freshly isolated lymphocytes of SLE patients was increased whereas levels of circulating apoptotic cells were comparable between patients and controls. Stimulation with anti-CD3 resulted in up-regulation of membrane Fas in patients and in controls. In vitro induction of apoptosis by anti-CD3 as well as by anti-Fas occurred both in SLE patients and controls, and was higher in SLE patients after incubation with anti-CD3 as well as with anti-Fas. We conclude that Fas expression and in vitro induction of apoptosis are increased in SLE even in the absence of disease activity.
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PMID:Anti-CD3-induced and anti-Fas-induced apoptosis in systemic lupus erythematosus (SLE). 1116 9

Induction of MHC class I genes in neurons of the central nervous system requires signals by pro-inflammatory cytokines, in particular IFN-gamma, and the blockade of electric activity, which is known to suppress induction of MHC related genes in a highly ordered, but unusual fashion [1], [2]. The present experiments explore the immunological function of neuronal MHC class I antigens expressed under permissive conditions. MHC class I proteins were induced in electrically silenced murine hippocampal neurons by treatment with the sodium channel blocker tetrodotoxin and recombinant IFN-gamma, conditions which also resulted in the induction of Fas molecules. The MHC class I positive neurons were challenged with CD8+ cytotoxic T lymphocytes (CTL) specific for the H2-Db binding peptide GP33, a dominant epitope of the lymphocytic choriomeningitis virus envelope glycoprotein, or with alloreactive CTL. Single primed neurons, attacked by GP33-specific CTL, were continuously monitored for changes in intracellular calcium ([Ca2+]i), an indicator of cytotoxic damage. MHC class I-induced neurons pulsed with the GP33 peptide, but not a control peptide, showed a gradual and sustained increase in [Ca2+]i within 3 h following attack by GP33-specific CTL, while in astrocytes [Ca2+]i elevation was rapid. The slow course of the neuronal response was consistent with a delayed apoptotic killing mechanism rather than rapid granule-mediated plasma membrane lysis. Indeed, the attacked neurons bound annexin V, indicating membrane alterations preceding apoptotic cell death. In further support of apoptotic cell death, this sustained increase of [Ca2+]i levels was also observed following attack by perforin-deficient CTL, but was not detected in neurons derived from mutant lpr mice, which lack functional Fas molecules.
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PMID:MHC class I-restricted killing of neurons by virus-specific CD8+ T lymphocytes is effected through the Fas/FasL, but not the perforin pathway,. 1116 5

To investigate the effect of Nef on Fas-mediated apoptosis, we compared T cells, both population and subclones stably expressing Nef from HIV-1(NL432), with Nef(-) control cells. Fas-mediated apoptosis was significantly delayed in Nef(+) cells as determined by annexin V staining and the percentage of apoptotic cells was lower in all Nef-expressing cells than in the control cells by a maximum of 10-fold. Next we measured cell surface levels of Fas to test whether the delayed apoptosis in Nef(+) cells was due to reduced cell surface expression of Fas. We found that there was no significant difference in the surface level of Fas between the Nef(+) and Nef(-) cells. To further define the steps affected by Nef in the Fas signaling pathway, the activation of caspase-3 and caspase-8 was investigated. A reasonable correlation was found between the magnitude of apoptosis measured by annexin V staining and the enzymatic activity of caspase-3. The overall level of caspase-8 activity in Nef(+) cells was also lower than in Nef(-) cells, although the extent of inhibition was not as significant as seen for caspase-3. Overall, our results indicate that long-term stable expression of Nef, which mimicks persistent or latent infection in vivo, confers resistance against anti-Fas Ab-induced apoptosis through inhibition of caspase-3 and caspase-8 activation.
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PMID:Stable expression of human immunodeficiency virus type 1 Nef confers resistance against Fas-mediated apoptosis. 1117 89

Inflammation is characterized by an excess of cell proliferation often leading to fibrosis and sclerosis with subsequent loss of organ function. We hypothesized that these features may be ameliorated by induction of cell cycle arrest and apoptosis as result of therapy with matrix metalloproteinase (MMP) inhibitors. In our study, mesangial cells and experimental mesangial proliferative glomerulonephritis provided the model of inflammation. First, we investigated the effect of the MMP inhibitor BB-1101 in anti-Thy1.1 nephritis. The numbers of apoptotic glomerular cells in nephritic rats increased about 4 and 6 times as a result of BB-1101 therapy, observed 11 and 14 days after induction of disease, respectively. Subsequently, rat mesangial cells were exposed to an MMP inhibitor in vitro. Fluorescence-activated cell sorter analyses of cells exposed to RO111-3456 demonstrated a dose-dependent cell cycle arrest in the G(0)/G(1) phase associated with increased expression of statin. The cell cycle arrest was followed by apoptosis as investigated by terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) biotin nick-end labeling (TUNEL) and acridine orange/ethidium bromide stainings, as well as by annexin V binding. The induction of p53, p21, and bax, but not the Fas/FasL pathway appeared to play an important pathogenetic role. In summary, MMP inhibitors induce cell cycle arrest followed by apoptosis in mesangial cells. These features help to explain the anti-inflammatory effects of these compounds, such as reduction of mesangial cell proliferation and attenuation of extracellular matrix accumulation. In conclusion, induction of cell cycle arrest with subsequent apoptosis may offer new perspectives in the therapy of inflammation even beyond kidney diseases.
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PMID:Matrix metalloproteinase inhibitors cause cell cycle arrest and apoptosis in glomerular mesangial cells. 1125 28

Tachyplesin is an antimicrobial peptide present in leukocytes of the horseshoe crab (Tachypleus tridentatus). In this study, a synthetic tachyplesin conjugated to the integrin homing domain RGD was tested for antitumor activity. The in vitro results showed that RGD-tachyplesin inhibited the proliferation of both cultured tumor and endothelial cells and reduced the colony formation of TSU prostate cancer cells. Staining with fluorescent probes of FITC-annexin V, JC-1, YO-PRO-1, and FITC-dextran indicated that RGD-tachyplesin could induce apoptosis in both tumor and endothelial cells. Western blotting showed that treatment of cells with RGD-tachyplesin could activate caspase 9, caspase 8, and caspase 3 and increase the expression of the Fas ligand, Fas-associated death domain, caspase 7, and caspase 6, suggesting that apoptotic molecules related to both mitochondrial and Fas-dependent pathways are involved in the induction of apoptosis. The in vivo studies indicated that the RGD-tachyplesin could inhibit the growth of tumors on the chorioallantoic membranes of chicken embryos and in syngenic mice.
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PMID:RGD-Tachyplesin inhibits tumor growth. 1128 11

Expression of T-cell receptor- or Fcgamma receptor III-associated signal-transducing zeta chain is important for the functional integrity of immune cells. We found that significantly higher proportions of circulating CD3+ T cells as well as natural killer cells had low or absent expression of the zeta chain in patients with advanced melanoma than in normal donors (P < 0.0005). Decreased zeta expression was always observed in a small subset of circulating CD3+ T cells that were in the process of apoptosis, i.e., bound Annexin V or were terminal deoxynucleotidyl transferase-mediated nick end labeling positive. Up to 80% of T cells in the peripheral blood of patients with melanoma were Fas+, with the mean percentage of Fas+CD3+ cells significantly higher in patients (P < 0.004) than normal controls. These Fas+CD3+ T cells were found to preferentially undergo apoptosis. Annexin V binding, the loss of Fas expression from the cell surface as well as zeta down-regulation, which are associated with early apoptosis, were detected in a proportion of circulating Fas+CD3+. In Jurkat cells incubated with agonistic anti-Fas antibody (CH-11), a rapid loss of Fas expression from the cell surface coincided with Annexin V binding and preceded the loss of zeta chain during early apoptosis. In a subset of Jurkat cells coincubated with human melanoma cells, Annexin V binding and zeta degradation as well as DNA fragmentation were observed, indicating that the tumor induced T-cell death. Triggering of death receptors expressed on activated T lymphocytes was accompanied by the loss of zeta expression. On the other hand, soluble factors secreted by melanoma cells induced down-regulation but no apoptosis in activated normal T cells. In the circulation of patients with melanoma, apoptosis of immune effector cells may be related to the state of chronic activation, resulting in the up-regulation of death receptors and increased susceptibility to apoptosis.
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PMID:Decreased zeta chain expression and apoptosis in CD3+ peripheral blood T lymphocytes of patients with melanoma. 1130 Apr 96

It has been reported that apoptotic cells are increased in the peripheral blood from patients with systemic lupus erythematosus (SLE), where dysfunctions of T helper 1 (Th1) cells are known. In order to study whether apoptosis of Th1 cells is associated with the pathogenesis of SLE, early apoptotic cells in various T-cell subsets were detected using fluorescence-labeled annexin V (AnV). AnV binding was most frequently observed in CD4+CCR5+ T cells, and AnV binding rate (%) in this subset was higher in SLE than in normal controls (14.7 +/- 2.6), although that in active SLE (43.6 +/- 7.3) tended to be lower than that in inactive SLE (48.0 +/- 6.8). CD95/Fas expression was also increased in both active and inactive SLE. In some SLE patients, AnV binding rate changed in inverse proportion to titer of the serum anti-DNA antibody and in proportion to serum complement activity. These data suggest that apoptosis in Th1 cells is important in the pathogenesis of SLE and might play a role in regulating over-activation or autoreactive responses by T cells.
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PMID:A possible role of apoptosis for regulating autoreactive responses in systemic lupus erythematosus. 1134 Nov 5

Certain anti-Fas antibodies, such as RMF2, induce apoptosis of Fas-expressing cells. We applied the Fas/anti-Fas system to induce killing of Fas-expressing immunocytes with resultant immunosuppression. W7TM-1 tumour cells, a rat T-cell line, were inoculated subcutaneously in BALB/c mice and tumour growth was monitored in untreated mice and in mice treated with RMF2. Prior to treatment with RMF2, we examined the expression of Fas in isolated splenocytes and in tumour-infiltrating lymphocytes by flow cytometry and immunohistochemistry, respectively. There was a remarkable increase in Fas-positive lymphocytes, including natural killer (NK) cells, among splenocytes at day 5 after tumour cell inoculation. The number of Fas-positive infiltrating lymphocytes also increased markedly, from day 5 to day 10. We then examined whether RMF2 could induce apoptosis of Fas-positive activated lymphocytes isolated from the spleen at day 5 in vitro. Terminal deoxy (d) -UTP nick end labelling (TUNEL) and Annexin V staining methods showed apoptosis of isolated cells when incubated with RMF2, and typical apoptotic features were confirmed by 4',6-diamidino-2-phenylindole dihydrochloride (DAPI) staining. Furthermore, suppression of cellular and humoral immunity was noted in RMF2-treated mice by mixed lymphocyte reaction and assay of serum levels of immunoglobulin G, respectively. Finally, treatment of animals with RMF2 daily from day 5 to day 9 could maintain the tumour size, while the tumour mass began to diminish in untreated mice immediately after reaching a maximum size. We confirmed the enhancing effects of long-term treatment with RMF2, through the induction of immunosuppression, on the growth of unvascularized xenogeneic tumour cell grafts.
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PMID:Partial tolerance of subcutaneously transplanted xenogeneic tumour cell graft by Fas-mediated immunosuppression. 1138 Jun 95

To evaluate the importance of Ly49A on TCR-induced cellular events, we established clones of the 1F2 T cell hybridoma expressing either Ly49A or a chimeric version, Ly49A/H, where the Ly49A cytoplasmic domain has been replaced by the Ly49H cytoplasmic domain. Ligation of Ly49A, but not Ly49A/H, with its ligand H-2D(d) or anti-Ly49A mAbs caused a specific inhibition of TCR/CD3-induced IL-2 secretion. Moreover, flow cytometry analysis of hypodiploid DNA and annexin V binding revealed that ligation of Ly49A protected cells from apoptosis induced by anti-CD3 mAbs or Ag. In contrast, ligation of the Ly49A/H chimeric receptor had no antiapoptotic effect. In addition, engagement of Ly49A selectively inhibited TCR-induced Fas ligand expression whereas TCR-induced Fas expression was not significantly affected. Expression of Ly49 inhibitory receptors on T cells may represent an important mechanism for the regulation of T cell survival in vivo by inhibiting TCR-induced apoptosis and IL-2 secretion.
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PMID:Cutting edge: Ly49A inhibits TCR/CD3-induced apoptosis and IL-2 secretion. 1141 24


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