Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.1.1.148 (Thy1)
 1,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The murine gld mutation is targetted to the gene coding for the ligand of the Fas receptor for apoptosis. Gld mice display a lymphoproliferative and autoimmune syndrome that can be transferred in both irradiated euthymic wild and athymic beige (nubg) recipients. In order to test whether a supply of normal wild cells could correct the development of the gld syndrome, nubg mice were grafted with mixtures of gld and wild spleen cells from congenic donors which differed for the allotypes of the T-cell Thy1 membrane glycoprotein and/or of the B-cell Ig heavy chain. In the nubg chimeras, the wild spleen cells could down-regulate the hyperactivation of the B cells and the proliferation of the gld T cells, but this was not due to total eradication of the gld T-cell subset. Since this occurred in an athymic recipient, the correction of the gld syndrome did not require wild stem cell differentiation within a thymic environment, but should only depend on a sufficient Fas ligand supply by normal wild cells. Since the gld cells could proliferate in the nubg environment, the nubg environment could not provide sufficient Fas ligand to regulate the gld cell proliferation. Thus, the nubg B cells might lack Fas ligand expression, or express it but to a lower extent that T cells.
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PMID:Interactions of B6 wild and B6 gld cells engrafted within athymic nude beige recipients. 757 65

The lpr gene encodes a defective form of Fas, a cell surface protein that mediates apoptosis. This defect blocks apoptotic deletion of autoreactive T and B cells, leading to lymphoproliferation and lupus-like autoantibody production. The effects of the lpr Fas mutation on other kinds of physiologically relevant apoptosis are largely undocumented. To assess whether some of the apoptosis known to occur after ionizing radiation might be mediated by Fas/Fas ligand (FasL) interactions, we quantitated in vitro apoptosis by flow cytometry measurement of DNA content in splenic T and B cells from irradiated 5- to 8-month-old B6/lpr mice. Total apoptosis of both lpr and control cells was substantial after treatment; however there was a significant difference between B6 (73%) and lpr (25%) lymphocyte apoptosis. Thy1, CD4, CD8, and IgM cells from lpr showed much lower levels of apoptosis than control cells after irradiation. Apoptosis induced by heat shock was also impaired in lpr. The finding that gamma-irradiation increased Fas expression on B6 cells and that irradiation-induced apoptosis could be blocked with a Fas-Fc fusion protein further supported the possible involvement of Fas in this form of apoptosis. Fas/FasL interactions may thus play an important role in identifying and eliminating damaged cells after gamma-irradiation and other forms of injury.
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PMID:Radiation and stress-induced apoptosis: a role for Fas/Fas ligand interactions. 915 45

The most potent virulence factor of Pseudomonas aeruginosa, its exotoxin A (PEA), inhibits protein synthesis, especially in the liver, and is a weak T cell mitogen. This study was performed to correlate hepatotoxic and possible immunostimulatory features of PEA in vivo. Injection of PEA to mice caused hepatocyte apoptosis, an increase in plasma transaminase activities, and the release of TNF, IFN-gamma, IL-2, and IL-6 into the circulation. Most strikingly, liver damage depended on T cells. Athymic nude mice or mice depleted of T cells by anti-Thy1.2 mAb pretreatment failed to develop acute hepatic failure, and survival was significantly prolonged following T cell depletion. Neutralization of TNF or lack of TNF receptors prevented liver injury. In the liver, TNF was produced by Kupffer cells before hepatocellular death occurred. After T cell depletion, Kupffer cells failed to produce TNF. Transaminase release was significantly reduced in perforin knockout mice, and it was even elevated in lpr/lpr mice. These results demonstrate that PEA induces liver damage not only by protein synthesis inhibition but also by TNF- and perforin-dependent, Fas-independent, apoptotic signals.
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PMID:Acute hepatotoxicity of Pseudomonas aeruginosa exotoxin A in mice depends on T cells and TNF. 982 May 56

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

Mesangial cells play a prominent role in renal inflammatory disorders, especially in IgA nephropathy. This disease represents the most common form of glomerulonephritis that eventually leads to progressive kidney failure requiring renal replacement therapy. In kidney transplants, IgA nephropathy displays a high recurrence rate in the order of 50%. Increased cell proliferation rates and extracellular matrix (ECM) accumulation are crucial targets in the therapy of glomerulonephritis, including IgA nephropathy. The active role of matrix metalloproteinases (MMP) in the regulation of these two features is rapidly emerging. We studied a model of a specific type of mesangial cell-mediated glomerular inflammation, such as experimental mesangial proliferative glomerulonephritis and cultured proliferating mesangial cells. In addition, these tools allowed us to evaluate a new therapeutic strategy based on MMP inhibition. Inhibition of MMP activity and synthesis by antisense technology and by a synthetic inhibitor in vitro, successfully reverted the inflammatory mesangial cell phenotype to the physiologically existing resting state. In vivo, a hydramate-based MMP inhibitor attenuated excess mesangial cell proliferation and ECM accumulation in anti-Thy1.1 nephritis. The anti-proliferative effect was achieved by the induction of cell cycle arrest followed by apoptosis, mediated by the induction of p53, p21 and bax, but not by the Fas/FasL pathway. In conclusion, MMP inhibitors provide a new approach to the therapy of inflammation probably even beyond the field of renal disorders.
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PMID:The role of matrix metalloproteinases in the activation of mesangial cells. 1218 Aug 53

During thymic selection 'mis-selected' CD8(+) T cells exit to the periphery where they are deleted by a Fas/FasL-mediated mechanism, presumably as a result of activation by self-antigens. In the absence of functional FasL, as is the case in autoimmune gld mice, these 'mis-selected' T cells develop into unique Thy1(+)CD4(-)CD8(-) TCRalphabeta(+)B220(+) lymphocytes [abnormal double negative T (DN T) cells]. Using bioactive FasL-bearing vesicles [FasL vesicle preparation (FasL VP)], we were able to induce acute apoptosis in freshly isolated lymphocytes and to demonstrate that peripheral lymphocytes of gld mice become more sensitive to the FasL-mediated apoptosis as they age. Furthermore, flow cytometric analyses indicated that within this peripheral lymphocyte population, the abnormal DN T cells were preferentially eliminated. The exquisite sensitivity of these abnormal DN T cells is attributed to their increased membrane Fas expression with a concomitant reduction of cytosolic FLIP(L). Our data support the hypothesis that specific components of the Fas-mediated apoptotic pathway are modulated in favor of the elimination of auto-reactive T cells as well as those CD8(+) T cells that are 'mis-selected' in the thymus and escape to the periphery.
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PMID:Changes in sensitivity of peripheral lymphocytes of autoimmune gld mice to FasL-mediated apoptosis reveal a mechanism for the preferential deletion of CD4-CD8-B220+ T cells. 1509 79

Thy-1-negative lung fibroblasts are resistant to apoptosis. The mechanisms governing this process and its relevance to fibrotic remodeling remain poorly understood. By using either sorted or transfected lung fibroblasts, we found that Thy-1 expression is associated with downregulation of anti-apoptotic molecules Bcl-2 and Bcl-xL, as well as increased levels of cleaved caspase-9. Addition of rhFasL and staurosporine, well-known apoptosis inducers, caused significantly increased cleaved caspase-3, -8, and PARP in Thy-1-transfected cells. Furthermore, rhFasL induced Fas translocation into lipid rafts and its colocalization with Thy-1. These in vitro results indicate that Thy-1, in a manner dependent upon its glycophosphatidylinositol anchor and lipid raft localization, regulates apoptosis in lung fibroblasts via Fas-, Bcl-, and caspase-dependent pathways. In vivo, Thy-1 deficient (Thy1-/-) mice displayed persistence of myofibroblasts in the resolution phase of bleomycin-induced fibrosis, associated with accumulation of collagen and failure of lung fibrosis resolution. Apoptosis of myofibroblasts is decreased in Thy1-/- mice in the resolution phase. Collectively, these findings provide new evidence regarding the role and mechanisms of Thy-1 in initiating myofibroblast apoptosis that heralds the termination of the reparative response to bleomycin-induced lung injury. Understanding the mechanisms regulating fibroblast survival/apoptosis should lead to novel therapeutic interventions for lung fibrosis.
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PMID:Thy-1 interaction with Fas in lipid rafts regulates fibroblast apoptosis and lung injury resolution. 2816 68