Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.6 (RNA polymerase)
34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gadolinium chloride (GdCl3) is commonly used to deplete the liver of Kupffer cells (KC) and has been shown to decrease hepatic phagocytic activity and to abolish hepatic expression of certain KC-specific antigens. However, the exact fate of the KCs after GdCl3 treatment remains unclear. To determine if GdCl3 actually decreases the total number of KCs in the liver, we labeled phagocytically-active KC by administering fluorescent-labeled latex beads to rats treated with either normal saline or GdCl3. Total hepatic fluorescence and the distribution of fluorescence within liver acini were evaluated by intravital microscopy. Hepatic mRNA levels of KCR, a KC-specific gene product, and Pu-1, a ubiquitous monocyte gene product, were assessed by Northern blot analysis, and differences in the expression of pro-inflammatory (tumor necrosis factor (TNF)-alpha) and anti-inflammatory (interleukin (IL)-10) cytokines were assessed by reverse-transcriptase polymerase chain reaction (RT-PCR). Our results indicate that GdCl3 does not significantly reduce the number of phagocytically active cells in the liver, but alters the acinar distribution of these cells and may provoke a switch in the KC phenotype such that these cells no longer express KCR or IL-10. GdCl3 pretreatment inhibited stress-related induction of IL-10, but failed to down-regulate expression of TNF-alpha. This phenotypic change is likely to have important consequences because it permits relative overexpression of TNF-alpha.
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PMID:Gadolinium chloride alters the acinar distribution of phagocytosis and balance between pro- and anti-inflammatory cytokines. 890 39

The term myelodysplasia (MDS) refers to a group of bone marrow failure syndromes which are relatively rare in childhood. The pathogenesis of MDS is unknown, but a variety of chromosomal, molecular, and cytochemical abnormalities have been reported. We describe a 4-month-old female with MDS who presented with severe neutropenia and refractory anemia with excess blasts (RAEB). Bone marrow progenitor cell assays showed decreased erythroid and myeloid colony formation as compared to normal marrow, and the patient's serum further diminished colony formation of both her own and control marrow. These observations suggested the presence of a soluble factor inhibitory to hematopoiesis. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis of total RNA derived from the patient's bone marrow mononuclear cells revealed highly elevated tumor necrosis factor-alpha (TNF-alpha) mRNA levels. Using a similar RT-PCR profile, TNF-alpha mRNA levels were found to be elevated in two other children with myelodysplasia. We conclude that TNF-alpha is produced in large amounts by bone marrow mononuclear cells of children with MDS, and we hypothesize that TNF-alpha plays an important role in the pathophysiology of the ineffective hematopoiesis observed in MDS.
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PMID:Tumor necrosis factor-alpha suppresses hematopoiesis in children with myelodysplasia. 895 Mar 41

The ancient drug colchicine has repeatedly been proposed as a novel drug for therapy of pulmonary fibrosis. The present study was undertaken to add to the knowledge on colchicine's antiinflammatory and antifibrotic properties and thus help determine its actual rank in the treatment of pulmonary fibrosis. In vitro cell culture experiments with stimulated and unstimulated normal donor peripheral blood mononuclear cells (PMNC) and a human lung fibroblast cell line (WI-38) were used to determine the effects of colchicine on PMNC cytokine release (interleukin-6 and tumor necrosis factor-alpha) as well as on fibroblast proliferation and collagen synthesis rates. Reverse transcriptase polymerase chain amplifications of alpha 1 (III) collagen were done to detect collagen messenger ribonucleic acid (mRNA) expression. Colchicine did not significantly modulate tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) release of PMNC. Colchicine inhibited fibroblast proliferation and total collagen synthesis significantly at concentrations obtainable in serum in vivo. Transcription of the alpha 1 (III) collagen gene into mRNA continued under colchicine. We conclude that colchicine is a potent in vitro inhibitor of fibroblast functions in terms of proliferation and collagen synthesis. The mechanism of collagen inhibition is more likely an inhibition of cellular collagen secretion than a switch off of collagen mRNA transcription. On the other hand, although colchicine is known to inhibit many leukocyte functions, it is a poor inhibitor of cytokines known to be important for fibrogenesis (e.g. IL-6, TNF-alpha, IL-1, platelet-derived growth factor, and transforming growth factor-beta). This makes colchicine, at least from a theoretical standpoint and as concluded from in vitro studies, a preferable candidate for a combined therapeutic strategy.
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PMID:Antiinflammatory and antifibrotic properties of colchicine: implications for idiopathic pulmonary fibrosis. 895 72

The herpes simplex virus thymidine kinase gene (HSV-TK) in combination with ganciclovir (GCV), is currently being used in gene therapy-based clinical trials for cancer treatment. Its therapeutic effect is based on a "bystander effect" whereby HSV-TK gene-modified tumor cells are toxic to nearby unmodified tumor cells when exposed to the antiviral drug GCV. We have recently hypothesized that the in vivo mechanism of this bystander effect is due to alterations in the tumor microenvironment in response to release of cytokines and an infiltration of leukocytes after treatment with HSV-TK gene-modified tumor cells and GCV, which results in tumor regression. Expression of B7, a recently identified costimulatory molecule that is important for T-cell stimulation, has been shown to be modulated by stimulatory cytokines interferon-gamma, tumor necrosis factor-alpha, and inhibited by interleukin-10. In the present study, we investigated whether the cytokines released after HSV-TK and GCV treatment could include the expression of the costimulatory molecules B7-1 and B7-2 and the adhesion molecule (ICAM)-1 in the tumor. Furthermore, we investigated whether this altered environment affected the antitumor properties of host lymphocytes. An in vitro model was developed to establish the effects of HSV-TK gene-modified tumor cells and GCV on tumor infiltrating cells. The murine macrophage cell line (IC21) was exposed to either supernatants or cell lysates collected from a mixture of HSV-TK-transduced (KBALB-STK) and non-transduced (KBALB) murine fibrosarcoma tumor cells previously exposed to GCV (experimental). Immunohistochemical analysis showed a significant expression (P < .0001) of B7-1 and B7-2 post exposure of IC21 cells to either supernatant or lysate. In contrast, the level of expression in IC21 cells exposed to the control lysate or supernatant remained unchanged for B7-1 and B7-2. In vivo analysis for B7-1 and B7-2 expression by immunohistochemistry in tumor tissues from experimental mice receiving HSV-TK gene-modified tumor cells and GCV treatment showed a significant expression of B7.1 (35%, P < .0001) and B7.2 (38.2%, P < .0001) on tumor-infiltrating mononuclear cells. In contrast, tumor-bearing control animals showed low levels of B7-2 expression (5.8%), whereas B7-1 was undetectable, as confirmed by reverse-transcriptase polymerase chain reaction. In addition, a significant up-regulation of ICAM expression (50%) on tumor tissues was observed in the experimental group (P = .0317) as compared with the control group (25%). Furthermore, T cells isolated from experimental mice showed a significant in vitro proliferative response (p = .0202) when exposed to syngeneic tumor cells as compared with the control group. These data demonstrated that the use of HSV-TK gene-modified tumor cells and GCV as a suicide gene in the treatment of an intraperitoneal tumor resulted in the expression of the B7 costimulatory molecules and ICAM-1 adhesion molecule and enhanced proliferative response of host T cells. These findings help to understand the mechanism of tumor cell killing in vivo using HSV-TK gene-modified tumor cells.
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PMID:Expression of costimulatory molecules: B7 and ICAM up-regulation after treatment with a suicide gene. 898 40

This study examines how interleukin-6 (IL-6) expression by human luteinizing granulosa cells is regulated. IL-6 was assayed in culture supernatants, mRNA in cells by in situ hybridization and by a competitive reverse-transcriptase polymerase chain reaction (RT-PCR). TNF alpha (100 pg-1 ng/ml) induced IL-6 mRNA and protein. Phorbol 12-myristate 13-acetate (PMA) (50 nM) mimicked this effect. DibutyrylcAMP (1 mM) and 10 microM forskolin. C2-, C6- and C8-ceramide (15 microM), all had no effect. The inhibitor of protein tyrosine kinase (PTK), genistein (100 micrograms/ml) reduced tumor necrosis factor (TNF) effects. The inhibitors of protein kinase C (PKC) (staurosporine, 10 nM), of phospholipase C (U73122, 2 microM), of phospholipase A2 (PLA2), (indomethacin 30 microM, mepacrin 50 microM, nordihydroguaiaretic acid 10 microM, ONO-RS-082 3,5 microM), none prevented it. Hence, IL-6 is induced by TNF alpha via activation of PTK. Protein kinase A, phosphoinositide and conventional PKC, sphingomyelin and PLA2 pathways are not implicated.
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PMID:Tumor necrosis factor-alpha induces interleukin-6 mRNA and protein in human granulosa luteinizing cells via protein tyrosine kinase without involving ceramide. 908 55

Granulocyte-macrophage colony-stimulating factor, mobilized peripheral blood stem cell (PSC) products, and peripheral blood leukocytes posttransplantation contain cells that cause allogeneic and autologous T cell apoptosis. Isolation and characterization of these cells demonstrated that they were low-density (Percoll fractionation) CD14+ monocytes. T cells in PSC products have a depressed phytohemagglutinin (PHA) mitogenic response; however, purified CD4+ or CD8+ T cells exhibit a statistically normal mitogenic function. Furthermore, no T cell inhibitory activity was observed in CD14+, CD4+, and CD8+ cell-depleted fractions enriched in CD4- CD8- TCR alpha/beta+ T cells. Inhibition of T cell function by CD14+ monocytes required cell-cell contact, and the analyses of DNA fragmentation by Southern and TUNEL analysis demonstrates an activation-induced T cell apoptosis in the presence of CD14+ monocytes. Reverse-transcriptase polymerase chain reaction studies suggested that high levels of interleukin-10 or tumor necrosis factor gene transcripts in the PSC products may contribute to the inhibition of T cell function.
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PMID:Monocytes from mobilized stem cells inhibit T cell function. 912 7

We have treated DBA/2-->C57BL/6 murine cardiac allograft recipients with anti-CD4 monoclonal antibody or with gallium nitrate to promote long-term (>60 days) allograft survival. Within this period, all grafts developed histologic evidence of ongoing vascular and parenchymal tissue remodeling, including interstitial fibrosis and neointimal hyperplasia, which are characteristic of chronic allograft rejection. To evaluate residual alloimmunity associated with the pharmacologic avoidance of acute graft rejection and the development of chronic tissue remodeling, we subjected these graft recipients to a battery of histologic and immunologic tests. Similar test results were obtained for graft recipients treated with either of the two immunosuppressive agents. All long-surviving allografts displayed histologic evidence of ongoing microvascular endothelial activation and interstitial leukocytic infiltration. Reverse transcriptase-polymerase chain reaction analyses demonstrated intragraft expression of mRNAs for interleukin (IL)-1, IL-2, IL-4, IL-6, tumor necrosis factor, interferon-gamma, and transforming growth factor-beta. All recipients had limiting dilution analysis-detectable, graft-reactive cytolytic T lymphocytes and helper T lymphocytes in their spleens and grafts, and all produced high titers of graft-reactive alloantibodies. In general, these observations indicate that (1) a similar immune status is achieved in long-surviving allografts and their recipients when either anti-CD4 monoclonal antibody or gallium nitrate was used for antirejection therapy, (2) this immune status is characterized by continuous, long-term inflammatory and immune processes that are qualitatively similar to those observed during acute allograft rejection, and (3) no specific immune responses developed selectively in long-term graft recipients to account for the avoidance of acute graft rejection or the development of chronic tissue remodeling in the graft.
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PMID:Prolonged murine cardiac allograft acceptance: characteristics of persistent active alloimmunity after treatment with gallium nitrate versus anti-CD4 monoclonal antibody. 913 72

We recently found that complement C3 is locally synthesized and secreted into the exocrine pancreas. In the present study, we attempted to demonstrate the secretion of complement C4 and factor B in the exocrine pancreas. In five samples of pancreatic fluid, both C4 and factor B proteins were detected by enzyme-linked immunosorbent assay (ELISA). Immunoblot analysis revealed the C4 and factor B molecules in pancreatic fluid to be identical with these molecules in serum. Reverse transcriptase (RT)-polymerase chain reaction (PCR) analysis in pancreatic carcinoma cell lines suggested ductal epithelial cells to be the local production sites of these proteins in the pancreas. The secretion of C4 and factor B in ductal cell lines (PANC-1 and MIA PaCa-2) was independently regulated by interleukin (IL)-1 beta, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma; C4 secretion was induced by IFN-gamma, whereas factor B secretion was induced by IL-1 beta, TNF-alpha, or IFN-gamma. These observations indicate that: (a) complement C4 and factor B are secreted into the exocrine pancreas, (b) ductal epithelial cells appear to be the site of C4 and factor B biosynthesis, and (c) local secretion of C4 and factor B in the pancreas is differentially regulated by IL-1 beta, TNF-alpha, and IFN-gamma.
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PMID:Biosynthesis and secretion of MHC class III gene products (complement C4 and factor B) in the exocrine pancreas. 921 52

The distribution of myeloid lineage-associated cytokine receptors and lysosomal proteins was analyzed in human CD34+ cord blood cell (CB) subsets at different stages of myeloid commitment by reverse-transcriptase polymerase chain reaction (RT-PCR). The highly specific granulomonocyte-associated lysosomal proteins myeloperoxidase (MPO) and lysozyme (LZ), as well as the transcription factor PU.1, were already detectable in the most immature CD34+Thy-1+ subset. Messenger RNA (mRNA) levels for the granulocyte-colony stimulating factor (G-CSF) receptor, granulocyte-macrophage (GM)-CSF receptor alpha subunit and tumor necrosis factor (TNF) receptors I (p55) and II (p75) were also detected in this subset in addition to c-kit and flt-3, receptors known to be expressed on progenitor cells. By contrast, the monocyte-macrophage colony stimulating factor (M-CSF) receptor was largely absent at this stage and in the CD34+Thy-1-CD45RA- subsets. The M-CSF receptor was first detectable in the myeloid-committed CD34+Thy-l-CD45RA+ subset. All other molecules studied were found to be expressed at this stage of differentiation. Different cocktails of the identified ligands were added to sorted CD34+Thy-1+ single cells. Low proliferative capacity was observed after 1 week in culture in the presence of stem cell factor (SCF) + Flt-3 ligand (FL) + G-CSF. Addition of GM-CSF to this basic cocktail consistently increased the clonogenic capacity of single CD34+Thy-1+ cells, and this effect was further enhanced (up to 72.3 +/- 4.3% on day 7) by the inclusion of TNF-alpha. In conclusion, the presence of myeloid-associated growth factor receptor transcripts in CD34+ CB subsets does not discriminate the various stages of differentiation, with the exception of the M-CSF receptor. In addition, we show that TNF-alpha is a potent costimulatory factor of the very immature CD34+Thy-1+ CB subset.
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PMID:Analysis of myeloid-associated genes in human hematopoietic progenitor cells. 932 52

Recent studies suggest that interleukin-6 (IL-6) is produced in the intestinal mucosa during sepsis and endotoxemia and that the enterocyte may be a source of IL-6 in these conditions. The regulation of IL-6 production in the enterocyte is not fully understood. We tested the hypothesis that IL-6 production in the enterocyte is regulated by proinflammatory cytokines. This was done by treating cultured Caco-2 cells, a transformed human intestinal epithelial cell line, with different concentrations of tumor necrosis factor-alpha (TNF-alpha), IL-1 beta, IL-6 or interferon-gamma (IFN-gamma). IL-6 production by the Caco-2 cells was determined by ELISA. The expression of IL-6 mRNA was determined by reverse-transcriptase polymerase chain reaction. IL-6 was not produced in unstimulated Caco-2 cells. Treatment of the Caco-2 cells with IL-1 beta resulted in a dose- and time-dependent stimulation of IL-6 production with a maximal effect noted at an IL-1 beta concentration of .5 ng/mL at 24 h. IFN-gamma alone did not stimulate IL-6 production but potentiated the effect of IL-1 beta in a synergistic fashion. Treatment of the Caco-2 cells with IL-1 beta induced expression of IL-6 mRNA with a response noticed after 30 min. TNF-alpha and IL-6 did not influence the production of IL-6 in the Caco-2 cells. The results suggest that enterocyte IL-6 production is stimulated by IL-1 beta and that this effect is potentiated by IFN-gamma. The regulation of IL-6 production in the enterocyte may be specific for IL-1 beta, since neither TNF nor IL-6 stimulated IL-6 production.
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PMID:Interleukin-1 beta and interferon-gamma regulate interleukin-6 production in cultured human intestinal epithelial cells. 932 25


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