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:3.1.27.5 (RNase)
17,967 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The use of a highly sensitive method of in situ hybridization capable of detecting one copy of IFN mRNA per cell showed that from 20-50% of the cells from the peritoneum and bone marrow of both normal pathogen-free and axenic mice exhibited grain counts significantly greater than background levels following hybridization with riboprobes specific for the mouse interferon-alpha (IFN-alpha), IFN-beta, or IFN-gamma genes. Labeling was shown to be specific, as the labeled probe was displaced by a 200-fold excess of the specific unlabeled probe but not by a 200-fold excess of an unrelated probe. Grain counts were reduced to background levels when cells were pretreated with ribonuclease prior to in situ hybridization. The extent of labeling with either IFN-alpha or IFN-beta-specific probes increased following i.v. inoculation of mice with the IFN-inducer Newcastle disease virus (NDV) whereas the degree of labeling observed with a probe specific for beta-actin remained unchanged. No significant differences were observed in the number of bone marrow or peritoneal cells that expressed IFN-alpha or IFN-beta mRNA from either high (C57B1/6) or low (BALB/c) IFN-producing strains of mice. The majority of IFN-alpha and IFN-beta-containing cells from both the bone marrow and peritoneum of normal pathogen-free and axenic mice resembled monocytes morphologically, whereas the majority of IFN-gamma mRNA-containing cells resembled small lymphocytes. In addition, in the bone marrow a number of large cells which resembled megacaryocytes were found to express high levels of IFN-alpha mRNA. Nuclear run-on assays showed that IFN-alpha and IFN-beta genes were actively transcribed in both bone marrow and peritoneal cells from normal and axenic mice. Low levels of de novo IFN-gamma RNA synthesis were detected in the nuclei of peritoneal cells only. The expression of IFN genes in individual cells in the tissues of normal animals may constitute a basis for the regulation of both homeostasis and host defense against virus infection and neoplastic cells.
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PMID:Specific interferon genes are expressed in individual cells in the peritoneum and bone marrow of normal mice. 137 9

Using the technique of in situ hybridization, we have shown that resting, unstimulated, human peripheral blood eosinophils, obtained from subjects with greater than 8% eosinophilia, transcribe and translate messenger RNA (mRNA) for interleukin-6 (IL-6). After incubation for 24 hours in culture medium alone, approximately 19% of eosinophils were positive for IL-6 mRNA. This may be a reflection of their in vivo activation, but also may suggest that the gene for this cytokine is constitutively expressed in eosinophils. After stimulation with interferon gamma (IFN gamma) (500 U/mL), the percentage of IL-6-mRNA+ cells increased to 51.3%. This was accompanied by an enhancement of intensity of the hybridization signals. The specificity of the IL-6 probe and the hybridization signals was confirmed by the use of an IL-6 sense probe and RNase pretreatment of cell preparations. Evidence for the translation of IL-6 mRNA was obtained by immunocytochemical staining. Normal and activated eosinophils gave IL-6-specific immunoreactivity with a polyclonal antihuman IL-6 antibody. A higher percentage of positive cells was detected among activated eosinophils than those treated with medium alone. Using a specific immunoenzymetric assay, we detected 190.15 +/- 18.1 and 403.32 +/- 213.6 pg/mL of IL-6 in supernatants of unstimulated and IFN gamma-treated (24 and 48 hours) eosinophils, respectively. These data indicate that eosinophils are an important cellular source of IL-6.
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PMID:Human eosinophils synthesize and secrete interleukin-6, in vitro. 152 Aug 76

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

Treatment of mouse L cells with mouse IFN gamma induced a cytoplasmic Ca-dependent protein kinase, which highly phosphorylated cellular enzymes such as phosphodiesterase and RNase in vitro. The kinase partially purified from IFN gamma-treated cells (100 units/ml, 12 h at 37 degrees C) was different from IFN-induced dsRNA-dependent protein kinase since it was dsRNA independent. The kinase may have played an important role in mediating IFN-induced biological effects, since cellular enzymes were found to alter enzyme activity after phosphorylation by the kinase in vitro.
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PMID:Interferon gamma-induced Ca-dependent protein kinase in mouse L cells. 618 56

Spontaneous production of insulin-like growth factor-I (IGF-I) by inflammatory macrophages contributes to aberrant wound healing, but little is known about regulation of IGF-I synthesis in myeloid cells. The T cell-derived cytokine interferon-gamma (IFN gamma) inhibits several fibrogenic and angiogenic components of the wound-healing response. We have used metabolic labeling of primary colony stimulating factor-1 (CSF-1)-derived macrophages and a transformed macrophage cell line (PU5-1R) followed by immunoprecipitation to demonstrate that synthesis of the 17 kilodalton (kDa) prepro-IGF-I protein by these cells is substantially inhibited by IFN gamma. An exon 4 IGF-I/beta-actin riboprobe expression cassette was used in RNase protection assays to show that IFN gamma also reduces steady state levels of IGF-I mRNA in three different populations of macrophages in a time- and dose-dependent manner. This effect is specific for IFN gamma because neither the IFNs-alpha/beta nor lipopolysaccharide (LPS) affects expression of steady state IGF-I transcripts. Down-regulation of IGF-I mRNA by IFN gamma is dependent on de novo protein synthesis and is abrogated by coculture with cycloheximide. Nuclear run-on assays revealed that elongation of IGF-I transcripts is absent in fresh bone marrow cells but is induced several-fold after cells are cultured for 6 days with CSF-1. Treatment of these CSF-1-derived macrophages with IFN gamma for 6 h substantially inhibits synthesis of IGF-I mRNA. Studies on the decay of IGF-I mRNA in PU5-1R macrophages treated with an RNA polymerase inhibitor confirmed that the decline in IGF-I steady state mRNA in IFN gamma-treated cultures arises from an inhibition of transcription rather than from a reduction in mRNA stability. Since a variety of inflammatory mediators can induce expression of IGF-I in macrophages, inhibition of macrophage IGF-I synthesis by IFN gamma provides a mechanism by which leukocytes regulate levels of this growth factor in their microenvironment.
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PMID:Interferon-gamma inhibits macrophage insulin-like growth factor-I synthesis at the transcriptional level. 777 81

Type I (alpha/beta) and type II (gamma) IFN enhance MHC class I gene expression through an IFN-responsive element (IRE) present in the 5' flanking region of the class I-a genes. Comparison of the 5' sequences between classical class I-a genes and T region class I-b genes reveals little homology except for presence of a potential IRE. We have found that cell surface expression of thymus leukemia Ag (TL) was up-regulated by IFN-gamma to a greater extent than H-2K,D in all TL+ T cell lines tested. In contrast, IFN-alpha/beta, which significantly increased H-2K and H-2D Ag expression, had only minor effects on TL expression. Resting peripheral T cells, which were considered to be TL- from previous studies, were found to express TL at a low level as determined by flow cytometry, immunoprecipitation, as well as polymerase chain reaction; the level of expression also could be elevated by IFN-gamma. To examine the control of TL gene transcription and its regulation by IFN-gamma, varying lengths of the T18d 5' flanking region were analyzed in chloramphenicol acetyl transferase assays. By deletion analysis, promoter activity and IFN-gamma responsiveness were localized to an 86-bp fragment that contains the IRE. Both responses were localized further to a 32-bp fragment that contained the IRE at its 3' end. RNase protection assays revealed two major transcription initiation sites, one immediately 5' of the IRE and another approximately 60 bp downstream. Furthermore, polymerase chain reaction analysis of mRNA from resting T cells, thymocytes, and T cell tumor lines confirmed the RNase protection data. Thus, transcription of T18d initiates much further upstream than the classical class I genes, can utilize an unusual promoter element, and can be elevated by IFN-gamma.
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PMID:Regulation of TL antigen expression. Analysis of the T18d promoter region and responses to IFN-gamma. 836 Apr 84

Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease in which cytokines are thought to play an important role in beta-cell destruction and immune regulation. A major target of beta-cell autoimmunity in IDDM is the enzyme glutamate decarboxylase (GAD). We hypothesized that cytokines in the insulitis lesion modulate the synthesis of GAD. This may, in turn, modify the rate of beta-cell destruction. Accordingly we cultured rat islets in the presence and absence of cytokines, and measured synthesis of both isoforms of GAD, GAD65 and GAD67, by [35S]methionine incorporation and immunoprecipitation with a rabbit antiserum that recognizes both GAD65 and GAD67. Incubation of islets with interleukin (IL)-1 beta (1 ng/ml, 24 h), tumour necrosis factor alpha (TNF-alpha; 200 units/ml, 24 h) or interferon gamma (IFN-gamma; 500 units/ml, 72 h) significantly decreased the synthesis of both GAD65 and GAD67, but reduced neither total protein synthesis nor insulin accumulation in the medium or content. Incubation of islets for 24 h in IFN-alpha (1000 units/ml), TNF-beta (50 ng/ml), IL 2 (1000 units/ml), IL-4 (100 ng/ml), IL-6 (10 ng/ml), IL-10 (20 ng/ml), IL-12 (10 ng/ml) or transforming growth factor beta 2 (TGF-beta 2; 5 ng/ml) did not significantly alter GAD65 or GAD67 synthesis. Inhibition of GAD65 and GAD67 protein synthesis by IL-1 beta, TNF-alpha or IFN-gamma was reversed by co-incubation with the nitric oxide synthase inhibitor, NG-monomethyl arginine (NMMA). Expression of both GAD65 and GAD67 mRNA, measured by RNase protection assay, was also decreased by IL-1 beta and completely restored to baseline levels by NMMA. Thus the synthesis of both isoforms of islet GAD is selectively decreased in the presence of IL-1 beta, TNF-alpha or IFN-gamma by a NO-mediated mechanism, probably at the level of cytokine gene transcription. As GAD autoimmunity has been previously shown to have a pathogenic role in an animal model of IDDM, its inhibition by cytokines might limit the immune response, thereby regulating the rate of beta-cell destruction in IDDM.
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PMID:Cytokine regulation of glutamate decarboxylase biosynthesis in isolated rat islets of Langerhans. 876 Mar 54

Trophoblast cells do not normally express major histocompatibility complex (MHC) class II antigens during placental development in either mice or rats. We have previously observed that in vivo treatment of pregnant mice with interferon-gamma (IFN gamma) induces immunohistochemically detectable class II cell surface expression in many maternal cell types, but not on placental cells or other cells of extra-embryonic origin. Both IFN gamma- and 5-azacytidine-induced placental class II expression have been reported in mice by other scientists, however, which made it important to further clarify this issue. The present study was performed to analyze whether treatment of pregnant mice with recombinant IFN gamma or the drug 5-azacytidine in vivo can induce detectable MHC class II Ab mRNA expression. A strain of transgenic mice carrying a cytomegalovirus-regulated MHC class II Abq transgene, which was strongly expressed in the placenta, was used as a positive control in all in situ hybridizations and ribonuclease protection analyses. All mice were analyzed on gestation Days 12.5 and 17.5. Treatment of pregnant mice with IFN gamma did not induce detectable class II expression in the placental cells, whereas the maternal decidua showed expression both at the mRNA and protein level. Similarly, treatment with 5-azacytidine did not induce class II expression in the placenta, while a slight increase in mRNA expression was detected in the maternal decidual and uterine tissues. These results strengthen the opinion that MHC class II mRNA cannot normally be induced in murine placental cells after IFN gamma or 5-azacytidine treatments.
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PMID:Lack of detectable major histocompatibility complex class II a beta-chain messenger ribonucleic acid in placentas of interferon-gamma- and 5-azacytidine-treated mice. 931 71

Interferon-tau (IFN-tau), a type I IFN structurally related to IFN-alpha, is regarded as the major antiluteolytic factor secreted by the conceptus of ruminant ungulate species before definitive trophoblast attachment and implantation. It mediates its effects by acting on the uterine endometrium, where it blunts the normal pulsatile production of PGF2alpha, presumably as a result of its binding to type I IFN receptors. In this study, we describe the complementary DNAs for the two known subunits, IFNAR1 and IFNAR2, of this receptor isolated from bovine and ovine endometrial complementary DNA libraries by homology cloning. Although there is extensive inferred amino acid sequence similarity between bovine and ovine IFNAR1 (92% identity) and between bovine and ovine IFNAR2 (88% identity), they have diverged extensively from the human receptor subunits (approximately 67% and approximately 58% identity, respectively). Despite these differences in primary structure, the respective subunits from all three species are organized similarly in their extracellular and cytoplasmic regions, and the bovine and ovine subunits have each retained a number of polypeptide motifs implicated in signal transduction. These uterine receptors also appear not to be splice variants. The cloned ovine IFNAR1 subunit, for example, possesses the expected four extracellular SD100 domains of full-length bovine and huIFNAR1, and only the homologs of the so-called long form (huIFNAR2c) of human IFNAR2 have so far been identified. RT-PCR procedures indicate that the messenger RNA for both subunits are found, not only in endometrium, but in all other tissues examined except those ofpreimplantation conceptuses, which presumably cannot respond to the IFN-tau they produce. Quantitative RNase protection assays of ovine endometrial RNA show that the expression of neither subunit changes greatly during the estrous cycle or pregnancy. These data suggest that the type I IFN receptor, which is expressed by the endometrium and binds IFN-tau, is probably not a structurally unusual form.
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PMID:Molecular cloning of ovine and bovine type I interferon receptor subunits from uteri, and endometrial expression of messenger ribonucleic acid for ovine receptors during the estrous cycle and pregnancy. 934 3

Interferon tau (IFN-tau) proteins are secreted by the ovine conceptus for a few days before definitive attachment of the trophoblast to the uterine epithelium and act to prolong luteal life span. Multiple genes encode for IFN-tau in sheep, but it remains unclear which genes are expressed during early pregnancy and whether the proteins encoded by these genes are equipotent. Three distinct ovine (ov) IFN-tau gene variants, p3, p6, and s4, were examined to determine whether they differed in gene expression and whether the proteins displayed different biological activities. By using RNase protection assays, full-length protected fragments were detected for p3 and p6 in approximately similar proportions in conceptuses flushed from the uterus at Days 12-13, Days 15-16, and Days 18-19 of pregnancy, but the amount of full-length protected s4 transcripts was 10% to 20% of that for p3 and p6. Partially protected probe fragments were also evident, presumably from probe hybridization to related ovIFN-tau transcripts. Recombinant proteins were generated and exhibited 34.2 (p3), 8.4 (p6), and 11.9 (s4) units (x 10(-7)) of activity per milligram of protein when tested on Madin-Darby bovine kidney cells. Antiproliferative activity on human Daudi cells varied considerably between the interferons, with p3 being 2000-fold more potent than s4. The interferons were injected into the uterine lumen of ewes from 10 to 18 days postestrus. The functional life span of the corpus luteum (CL) was increased (p = 0.02) by either 300 microg/day p3 (31.7 +/- 7.8 days) or 300 microg/day p6 (25.5 +/- 4.2 days), but not by 300 microg/day s4 (19.2 +/- 2.9 days), when compared to controls (15.8 +/- 0.6 days). Injection of 1 mg/day s4 did, however, increase (p = 0.02) CL life span (23.5 +/- 4.1 days). These data suggest that IFN-tau genes are not equally expressed in trophectoderm and that ovIFN-tau genes encode for proteins with significantly different biological potency.
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PMID:Different ovine interferon-tau genes are not expressed identically and their protein products display different activities. 947 15


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