Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04141 (granulocyte-macrophage colony-stimulating factor)
 6,790 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apoptotic cell death induced by cross-linking Fas receptor (FasR/CD95) has been investigated in human acute myelogenous leukemia (AML) cells. FasR-mediated growth inhibition and DNA fragmentation could be induced in certain cases of AML. Interestingly, when DNA synthesis and G1 -> S transition in the cell cycle were enhanced by interleukin-3 or granulocyte-macrophage colony-stimulating factor, Fas-insensitive blast cells acquired cellular susceptibility toward FasR-mediated growth inhibition. To further evaluate an association between the Fas-R-mediated action and a specific phase of the cell cycle, a FasR+ leukemic cell line, MML-1, was established from a patient with AML. The morphologic feature of dying cells and DNA fragmentation indicated that FasR cross-linking induced apoptotic cell death in MML-1 cells. Cell cycle arrest in G1A phase with the treatment of phorbol 12-myristate 13-acetate or thymidine rendered MML-1 cells resistant to FasR-mediated apoptosis without downregulation of surface FasR expression. However, S-phase arrest with 5-fluorouracil could neither enhance nor inhibit FasR-mediated apoptosis. Simultaneous DNA/RNA quantification analysis revealed the selective loss of cells in G1B compartment, accompanied by the increase of apoptotic nuclei in sub-G1 fraction. These findings suggested that FasR-mediated apoptotic signals could be transduced into cells in G1B compartment and G1A -> G1B transition might augment the induction of FasR-mediated apoptosis.
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PMID:Fas receptor (CD95)-mediated apoptosis is induced in leukemic cells entering G1B compartment of the cell cycle. 757 53

Bacterial superantigens are the most potent known activators of human T lymphocytes. To engineer superantigens for immunotherapy of human colon carcinoma, the superantigen, staphylococcal enterotoxin A (SEA) was genetically fused to the Fab region of the colon carcinoma-reactive monoclonal antibody C242. In the present study the effector mechanisms involved in the anti-tumor response to C242 Fab-SEA were characterized. Immunohistochemistry and computer-aided image analysis were used in studies of cryopreserved tumor tissue to evaluate the phenotype of infiltrating cells and their cytokine profiles in response to therapy. Human T cells and monocytes were recruited to the tumor area and penetrated the entire tumor mass within hours after injection of C242 Fab-SEA. The production of cytokines at the single-cell level was found to be dominated by tumor necrosis factor (TNF)-alpha, interleukin (IL)-2, IL-4, IL-5, IL-10, IL-12, interferon (IFN)-gamma, granulocyte-macrophage colony-stimulating factor, and transforming growth factor-beta, whereas IL-1-alpha, IL-1ra, IL-1 beta, TNF-beta, IL-3, IL-6, and IL-8 were undetectable. Most of the TNF-alpha, IL-2, IL-12, and IFN-gamma were made by the infiltrating human leukocytes, while the colon carcinoma cells were induced to produce IL-4, IL-10, and TNF-alpha. Up-regulation of IFN-gamma receptors and TNF R p60 receptors was found, while the TNF R p80 receptor was absent. The cytokine production, T cell infiltration, and CD95 Fas receptor expression concomitantly occurred to induce programmed cell death in the tumor cells. This was followed by a strong reduction of the tumor mass that was seen within 24 h after C242 Fab-SEA infusion. These findings demonstrate that antibody-superantigen proteins efficiently recruit tumor-infiltrating lymphocytes actively producing a variety of cytokines likely to be essential for the therapeutic effects observed in the model. Although the humanized SCID model has obvious limitations in its predictive value for treatment of human cancer, we believe that these results encourage clinical evaluation of antibody-targeted superantigens.
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PMID:Antibody-targeted superantigen therapy induces tumor-infiltrating lymphocytes, excessive cytokine production, and apoptosis in human colon carcinoma. 856 49

Mast cells (MC), blood basophils (Ba) and monocytes (Mo) are of haemopoietic origin. Lineage-relationships and transdifferentiation between MC and Mo, or MC and Ba, have been considered, based on common expression of antigens. In this study, comparative phenotypic analyses on MC, Ba and Mo and on respective cell lines were performed using monoclonal antibodies (mAb) to previously defined and novel CD antigens (CD1-130). By cluster analysis, the overall (all 130 CD) phenotypic relationships (given as similarity indices, SI), between primary cells (MC, Ba and Mo) and corresponding cell lines (HMC-1, KU-812, U937) were 0.716, 0.779 and 0.757, respectively. When primary cells were compared, lower SI values were found (MC versus Ba, 0.509; MC versus Mo, 0.625; Mo versus Ba, 0.698). More distant relationships were found between MC versus Ba and MC versus Mo, compared with Ba versus Mo, for adhesion receptor (R)-, complement R- and cytokine R profiles. Analysis of cytokine R revealed most significant dissimilarities between MC versus Ba and MC versus Mo (SI < 0.2). Moreover, in contrast to other CD subgroups and other lineages, MC and HMC-1 differed from each other in cytokine R expression (SI = 0.286). Cytokine R detectable on HMC-1 but not MC were granulocyte-macrophage colony-stimulating factor (GM-CSFR)alpha(CD116), CD40, Apo-1/FAS(CD95) and gp130(CD130). Cytokine R detectable on Ba but not MC, were interleukin-3 (IL-3)R alpha(CD123), IL-1RII(CD121b), IL-2R alpha(CD25) and CD40. In summary, MC, Ba and Mo display a unique CD profile with MC being the most distantly related cell. The most significant mismatch within a given lineage is the loss of cytokine R on mature MC as compared with normal myeloid progenitors and HMC-1 cells.
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PMID:Comparative immunophenotypic analysis of human mast cells, blood basophils and monocytes. 867 6

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 granulocyte-macrophage colony-stimulating factor (GM-CSF) analog E21R induces apoptosis of hemopoietic cells. We examined the GM-CSF receptor subunit requirements and the signaling molecules involved. Using Jurkat T cells transfected with the GM-CSF receptor we found that both receptor subunits were necessary for E21R-induced apoptosis. Specifically, the 16 membrane-proximal residues of the alpha subunit were sufficient for apoptosis. This sequence could be replaced by the corresponding sequence from the interleukin-2 receptor common gamma subunit, identifying this as a conserved cytokine motif necessary for E21R-induced apoptosis. Cells expressing the alpha subunit and truncated betac mutants showed that the 96 membrane-proximal residues of betac were sufficient for apoptosis. E21R, in contrast to GM-CSF, did not alter tyrosine phosphorylation of betac, suggesting that receptor-associated tyrosine kinases were not activated. Consistent with this, E21R decreased the mitogen-activated protein kinase ERK (extracellular signal-regulated kinase). E21R-induced apoptosis was independent of Fas/APO-1 (CD95) and required interleukin-1beta-converting enzyme (ICE)-like proteases. In contrast, Bcl-2, which protects cells from growth factor deprivation-induced cell death, did not prevent this apoptosis. These findings demonstrate the GM-CSF receptor and ICE-like protease requirements for E21R-induced apoptosis.
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PMID:The apoptosis-inducing granulocyte-macrophage colony-stimulating factor (GM-CSF) analog E21R functions through specific regions of the heterodimeric GM-CSF receptor and requires interleukin-1beta-converting enzyme-like proteases. 909 24

Binding of Fas ligand (FasL) or an agonistic anti-Fas receptor (Fas/CD95) antibody induces apoptosis in Fas-bearing target cells. The involvement of Fas/FasL pathway has been investigated in human acute myelogenous leukemia (AML) cells. Fas/CD95 is expressed on a majority of AML cells, although the intensity of expression is variable. The cross-linking with anti-Fas antibody can induce apoptotic cell death in certain cases of AML. When DNA synthesis and cell cycle progression are enhanced by growth-promoting cytokines, such as interleukin-3 and granulocyte-macrophage colony-stimulating factor, Fas-insensitive AML cells acquire cellular susceptibility toward Fas-mediated apoptosis. Cell cycle analysis reveals that Fas-mediated apoptotic signals can be transduced into cells in G1B compartment and G1A-->G1B transition might support the induction of Fas-mediated apoptosis. In addition, Fas-mediated apoptotic cell death of AML cells is also induced by interleukin-2-activated T cells expressing functional FasL on their surfaces. Activated T cells express a large amount of FasL mRNA, compared with freshly isolated T cells. The Fas/FasL pathway seems to be the major mechanism of T cell-mediated apoptosis in AML cells, although alternative mechanisms can also be operative. The induction of apoptosis in Fas/FasL system might be a novel and effective approach for leukemia immunotherapy.
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PMID:Fas receptor (CD95)-mediated apoptosis in leukemic cells. 913 Jun 10

Dendritic cells (DC) are considered to be the most potent antigen-presenting cells (APC) in the immune system. In this study, we analyzed the regulation of apoptosis of human peripheral blood-derived DC. DC were generated from adherent peripheral blood mononuclear cells that had been cultured for 7 days with granulocyte-macrophage colony-stimulating factor and interleukin-4. These cells displayed phenotypic properties of DC, including dendritic processes, expression of CD1a and lack of expression of CD14, and were very potent at presenting soluble antigens to T cells. Blood-derived DC were demonstrated to express the Fas/CD95 antigen and an agonist antibody to CD95 strongly induced apoptotic cell death in these cells. Soluble trimeric CD40 ligand potently inhibited both CD95-mediated and spontaneous apoptosis in DC. The data suggest that interactions between members of the tumor necrosis factor family of ligands expressed by T cells with their receptors on DC play an important role in the regulation of apoptosis in DC during antigen presentation and may, therefore, regulate the duration of T cell expansion and cytokine production.
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PMID:CD40 ligand inhibits Fas/CD95-mediated apoptosis of human blood-derived dendritic cells. 946 1

CD95 (Fas, APO-1) is a cell surface receptor expressed on many cells including eosinophils which mediates apoptosis when ligated by agonistic antibodies or its natural ligand FasL. Since inhibition of apoptosis may play an important role in controlling tissue eosinophilia, we investigated the expression of CD95 on purified peripheral blood eosinophils from normal donors. Freshly isolated eosinophils expressed CD95 on the cell surface as well as CD95-specific mRNA at low levels which did not change during 24-h culture. Incubation of eosinophils with IL-3, IL-5 and granulocyte-macrophage colony-stimulating factor (GM-CSF) did not modulate the basal expression of CD95. IFN-gamma as well as TNF-alpha, however, induced a significant, dose- and time-dependent increase in CD95 mRNA and cell surface expression as measured by reverse transcription-PCR and flow cytometry. Co-stimulation with IFN-gamma and TNF-alpha had synergistic effects on the CD95 surface expression on eosinophils. Addition of IL-3, IL-5 or GM-CSF to IFN-gamma- and TNF-alpha-stimulated eosinophils caused in a reduction of CD95 expression. Functional activity for CD95 following incubation with IFN-gamma and TNF-alpha was demonstrated by increased apoptosis in response to cross-linking with FasL. From these data, we conclude that IFN-gamma and TNF-alpha can up-regulate cell surface expression of CD95 on eosinophils, which leads to an increased susceptibility of eosinophils to Fas-mediated apoptosis. Thus, our results suggest that receptors involved in eosinophil apoptosis can be regulated by antagonistic cytokines.
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PMID:Differential regulation of CD95 (Fas/APO-1) expression in human blood eosinophils. 969 73

The CD95 (Fas/APO-1) apoptosis receptor is expressed in a variety of tissues and transiently upregulated in lymphocytes during activation-induced cell death. A silencer (S1; -1035 to -1008) and an adjacent enhancer (E1; -1007 to -964) region have been mapped in the CD95 gene. The S1 region shows similarity to binding sites for the transcriptional repressor NF-GMb, which prefers binding to single-stranded DNA. The E1 contains an everted repeat of two CATTA/T elements spaced by 2 bp (ER2). Such motifs are directly repeated in the CLE0 region of the human granulocyte-macrophage colony-stimulating factor (huGM-CSF) promoter. A motif (TGATGTCA) which matches a CREB site and is similar to an AP-1 site is embedded within ER2. Sequence-specific binding of nuclear factors to single-stranded S1 probes involved, to some extent, a central heptamer motif (ATCCAAA) also present in E1. Competition binding studies suggested that AP-1 or AP-1 components, as well as factors related, but not identical, to NF-AT bound to E1 probes. S1-binding-proteins/complexes of 47, 77, and 100 kDa were detected by Southwestern analysis and ultraviolet crosslinking. Complexes of 70 and 80 kDa were formed with a double-stranded E1 probe in UV-crosslinking, whereas Southwestern analysis with this probe revealed single binding species of 59 and 113 kDa. ER2 autonomously enhanced transcription from the heterologous HSV tk promoter in a cell type-specific manner only in the absence of the S1 region. This analysis has identified a small region in the CD95 gene containing adjacent opposing regulatory elements which are likely to be involved in the cell type- and activation state-specific gene expression under physiologic conditions.
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PMID:Silencer and enhancer regions in the human CD95 (Fas/APO-1) gene with sequence similarity to the granulocyte-macrophage colony-stimulating factor promoter: binding of single strand-specific silencer factors and AP-1 and NF-AT-like enhancer factors. 988 66

Tumor cells that survive initial courses of chemotherapy may do so by acquiring a multidrug-resistant phenotype. This particular mechanism of drug resistance may also confer resistance to physiological effectors of apoptosis that could potentially reduce the efficacy of immune therapies that use these pathways of cell death. We have previously demonstrated high efficacy for a cytokine-based tumor cell vaccine in a murine MPC11 myeloma model. In the present study, the effects of this vaccination were compared in MPC11 cells and their isogenic sublines selected for mdr1/P-glycoprotein (Pgp)-mediated multidrug resistance (MDR). Immunization with MPC11 cells expressing granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-12 (IL-12) led to long-lasting protection of mice against subcutaneous (sc) challenge with both parental cells or their MDR variants. Similarly, immunization with GM-CSF/IL-12-transfected MDR sublines caused rejection of transplantation of both parental cells and the MDR sublines. Whereas MPC11 cells and their MDR variants were resistant to APO-1/CD95/Fas ligand, the immunization generated potent granzyme B/perforin-secreting cytotoxic T lymphocytes (CTLs) that were similarly effective against both parental and isogenic MDR cells. We conclude that MDR mediated by mdr1/Pgp did not interfere with lysis by pore-forming CTLs. Immunotherapy based on pore-forming CTLs may be an attractive approach to the treatment of drug-resistant myeloma.
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PMID:Cytokine-based tumor cell vaccine is equally effective against parental and isogenic multidrug-resistant myeloma cells: the role of cytotoxic T lymphocytes. 1006 54


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