Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.27.4 (ribonuclease)
 6,621 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interferon-alpha (IFN) induces the enzyme 2-5 oligoadenylate synthetase (2-5 AS) in cells from patients with hairy cell leukemia and B-cell chronic lymphocytic leukemia and this is associated with a breakdown of certain species of cytokine messenger (m)RNA via the activation of a latent ribonuclease. We have studied the expression of the cytokines interleukin 1-beta (IL-1), interleukin 6 (IL-6), granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumour necrosis factor alpha (TNF) as well as of the ribonuclease activator 2-5 AS in the presence and absence of IFN in acute myeloid leukaemia (AML) blast cells from 26 patients. Before monocyte and T-cell depletion there was no expression of IL-1, IL-6 or GM-CSF, and only three of 13 patients studied expressed TNF mRNA. After cell depletion one or more cytokine was expressed in 31-62% of the 26 patients. Expression of one or more mRNA for IL-1, IL-6, GM-CSF and TNF after 18 h incubation was detected in 16 of 26 patients (63%) and this was particularly so in French-American-British (FAB) subtypes M4 and M5. Eight of nine patients with IL-6 mRNA expression and seven of 10 with IL-1 mRNA expression were in the FAB subtypes M4 and M5. Twenty-two of 26 patients showed induction of 2-5 AS mRNA in response to IFN in vitro. Exposure to IFN resulted in reduction of IL-1 mRNA in nine of 12 cases, of IL-6 mRNA in eight of nine, and GM-CSF mRNA in five of seven cases. TNF mRNA was unaffected by IFN despite 2-5 AS induction in 12 of 13 patients expressing this cytokine. In the presence of exogenous IFN, cells from six of seven patients studied showed inhibition of 3H-thymidine incorporation into DNA. DNA synthesis could also be abrogated in six of seven patients with anti-IL-1 monoclonal antibodies (MoAb) and in two of seven with anti-IL-6 MoAb. This inhibitory effect could be reversed in all patients when anti-IL-1 or anti-IL-6 was given in combination with their corresponding cytokine. These data suggest that IFN may exert a therapeutic effect in a proportion of AML patients by blocking IL-1 and IL-6 mediated growth, consequent on activation of the ribonuclease activator 2-5 AS.
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PMID:Effects of interferon-alpha (IFN) on the expression of interleukin 1-beta (IL-1), interleukin 6 (IL-6), granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumor necrosis factor-alpha (TNF) in acute myeloid leukemia (AML) blasts. 143 98

alpha 1-Antitrypsin (alpha 1 AT) is plasma glycoprotein that constitutes the principle inhibitor of neutrophil elastase in tissue fluids. It has been considered a prototype for liver-derived acute phase proteins in that its concentration in plasma increases three- to fourfold during the host response to inflammation/tissue injury. However, recent studies have shown that alpha 1 AT is expressed in several types of extrahepatic cells, including mononuclear phagocytes and enterocytes, and that there are distinct transcriptional units used in hepatocytes and at least one extra-hepatic cell type, blood monocytes. In this study, we have used a combination of ribonuclease protection assays, primer elongation analysis, and transcriptional run-on assays to further characterize mechanisms of basal and modulated alpha 1 AT gene expression in hepatocytes, enterocytes, and macrophages. The hepatoma cell line HepG2, intestinal epithelial cell line Caco2, and primary cultures of human peripheral blood monocytes were used as examples of the cell types. The results indicate that there are three macrophage-specific transcriptional initiation sites upstream from a single hepatocyte-specific transcriptional initiation site. Macrophages use these sites during basal and modulated expression. Hepatoma cells use the hepatocyte-specific transcriptional initiation site during basal and modulated expression but also switch on transcription from the upstream macrophage transcriptional initiation sites during modulation by the acute phase mediator interleukin 6 (IL-6). Caco2 cells use the hepatocyte-specific transcriptional initiation site during basal expression. There is a marked increase in the use of this site and an increase in the rate of transcriptional elongation of alpha 1 AT mRNA during differentiation of Caco2 cells from crypt-type to villous-type enterocytes. Caco2 cells also switch on transcription from the upstream macrophage transcriptional initiation sites during modulation by IL-6. These results provide further evidence that there are differences in the mechanisms of constitutive and regulated expression of the alpha 1 AT gene in at least three different cell types, HepG2-derived hepatocytes, Caco2-derived enterocytes and mononuclear phagocytes.
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PMID:Constitutive and modulated expression of the human alpha 1 antitrypsin gene. Different transcriptional initiation sites used in three different cell types. 155 83

The B lymphoproliferative disorders B chronic lymphocytic leukemia (B-CLL) and hairy cell leukemia (HCL) produce a number of autocrine growth factors, including tumor necrosis factor (TNF), interleukin 6 (IL-6), and IL-1, all of which may induce positive feedback growth loops. If such malignancies depend on these autocrine growth loops for survival, their interruption may be therapeutically valuable. Interferon alpha (IFN-alpha) abrogates TNF- or IL-6-induced proliferation of HCL and B-CLL cells in vitro and has therapeutic activity in these diseases. We have investigated the possibility that IFN-alpha may act by interrupting autocrine growth factor loops. If purified B-CLL or HCL cells are cultured in the presence of TNF, there is induction of mRNA for TNF, IL-1 alpha, IL-1 beta, and IL-6. However, culture in the presence of IFN-alpha in addition to TNF reduced the level of mRNA for all these cytokines, compared with cells cultured in TNF alone. While cytokine mRNA levels were diminished, levels of mRNA for the ribonuclease activator 2-5A synthetase were increased. Analysis of the kinetics of cytokine mRNA production showed that levels fall shortly after the rise of 2-5A synthetase mRNA. IFN-alpha may produce these effects by shortening the half-life of cytokine mRNA, since TNF mRNA half-life in B-CLL and HCL cells is substantially reduced when the cells are cultured with IFN-alpha. These data suggest that IFN-alpha may mediate its therapeutic effects in these malignancies by blocking autocrine growth factor loops.
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PMID:Effects of interferon alpha on autocrine growth factor loops in B lymphoproliferative disorders. 225 3

Keratinocyte growth factor (KGF), a member of the fibroblast growth factor family of related proteins, is expressed by stromal fibroblasts and acts on epithelial cells in a paracrine fashion. To understand the mechanisms responsible for regulating normal KGF expression and how these might be altered in disease, the 5'-flanking region of this gene was cloned. The presence of two KGF transcription initiation sites was suggested by ribonuclease protection assay and confirmed by primer extension analysis. Examination of the genomic DNA sequence revealed the presence of the putative promoter sequences TATTTA and CCAAT, located 31 and 50 base pairs upstream, respectively, from the first of the two mRNA start points, and putative initiator sequences surrounding each transcription start site. Transient transfection into murine NIH/3T3 fibroblasts demonstrated that the region required for basal level KGF promoter activity was located between bases -225 and +190. Inclusion of sequences between -1503 and -775 markedly reduced promoter activation, indicating the presence of negative regulatory element(s) in this region. A similar pattern of promoter activation was detected in human fibroblasts and in murine C2C12 myoblasts. In contrast, no chloramphenicol acetyltransferase activity was observed in macrophages and epithelial and lymphoid cells transfected with the same constructs. Northern blot analysis revealed a strong correlation between KGF RNA expression and promoter activation in all cells tested. Activation of the KGF promoter could be induced by the proinflammatory cytokines interleukin 1 and interleukin 6 and by the adenylate cyclase activator forskolin. Taken together, these results indicate the existence of cis-acting element(s) responsible for selective activation of the KGF promoter only in cells that express KGF mRNA and may provide a mechanistic basis for KGF gene expression during inflammation.
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PMID:Cloning and characterization of the promoter region of the human keratinocyte growth factor gene. 774 56

Plasma pancreatic-type Poly-C specific ribonuclease (P-RNase)-enzyme activity increases in patients with acute pancreatitis (AP) who develop pancreatic necrosis and severe disease course. It is considered as a marker of pancreatic tissue destruction. The aim of this study was to estimate interrelations between major inflammatory cytokines such as: interleukin 6 (IL-6), interleukin 8 (IL-8) and tumor necrosis factor soluble receptors: sTNFR55 and sTNFR75 output, and plasma P-RNase activity. The study was carried out in a group of 56 patients with AP, where 20 developed pancreatic necrosis. It was found that serum P-RNase concentration and levels of all studied inflammatory cytokines significantly increase already in the first day from diagnose of the disease (2.5 folds for P-RNase, 20 for IL-8, about 200 for IL-6 and 1.5 for receptors, respectively). In the first day from admission to hospital, P-RNase activity significantly correlated with plasma concentration of studied inflammatory cytokines. The most pronounced correlation was found for P-RNase and IL-6 in days 1-4 from diagnose, manifested by Pearson correlation r coefficients amounting to 0.86, 0.79, 0.60 and 0.57 respectively (p<0.001). Dividing the studied AP patients into two groups, varying in severity of disease a significant differences in P-RNase and IL-6, IL-8 and sTNFR55/sTNFR75 were found. In patients with acute necrotizing pancreatitis P-RNase significantly correlate with levels of major inflammatory cytokines. Carried out studies suggest that activity of P-RNase reflects severity of inflammatory reaction, which is dependent on development of pancreatic injury and tissue necrosis in AP.
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PMID:Poly-C specific ribonuclease activity correlates with increased concentrations of IL-6, IL-8 and sTNFR55/sTNFR75 in plasma of patients with acute pancreatitis. 1456 81