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)

Endothelial cells (EC) are very responsive to the proinflammatory cytokine interleukin-1 (IL-1). EC are induced by IL-1 to secrete chemotactic factors and to increase expression of cell surface adhesion molecules leading to increased leukocyte adhesion. Activated EC further contribute to the inflammatory response by secreting additional cytokines. IL-1 interacts with EC through high-affinity cell-surface receptors. However, the low number of receptors present on EC has made characterization difficult. Further, recent evidence has suggested diversity in the responses of EC from different regions of the vascular system. Interested in the effect of IL-1 on early atherosclerotic lesion formation, we have characterized the IL-1 receptors on human aortic endothelial cells (HAEC). Using a direct binding assay, we found that HAEC have 1,000-3,000 IL-1 receptors per cell and bind IL-1 alpha with a Kd of 3.5 x 10(-10) M. We found that a monoclonal antibody specific for the type I receptor completely blocks IL-1 alpha binding. The blocking antibody also completely inhibits the IL-1 induced increase in intracellular adhesion molecule 1 (ICAM-1) expression by HAEC. Using solution hybridization and ribonuclease protection with an antisense probe, a sensitive method for detection of low abundance mRNA species we found that HAEC as well as human umbilical vein EC (HUVEC) have significant levels of mRNA for the type I IL-1 receptor. To test whether HAEC might also contain transcripts for the type II IL-1 receptor, we compared levels of mRNAs by polymerase chain reaction (PCR) amplification of cDNAs reverse-transcribed from total RNA. We found only transcripts for the type I receptor and not the type II receptor in HAEC. Based on this data, we conclude that aortic endothelial cells respond to IL-1 through the type I receptor.
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PMID:Human aortic endothelial cells express the type I but not the type II receptor for interleukin-1 (IL-1). 136 15

Transforming growth factor (TGF)-beta and interleukin (IL)-10 inhibited lipopolysaccharide (LPS)-induced macrophage production of the inflammatory cytokines tumor necrosis factor-alpha (TNF), IL-1 alpha, and IL-1 beta by contrasting post-transcriptional mechanisms. TGF-beta acted slowly and late, as it required 12-16 h to exert a suppressive effect, and inhibited TNF production even when added 6 h after LPS. TGF-beta affected neither the level of TNF mRNA, the release of preformed TNF nor the degradation of TNF. Thus, TGF-beta appeared to inhibit translation of TNF mRNA. IL-10 not only suppressed TNF release to a 25-fold greater extent than TGF-beta, but also inhibited release of IL-1. In contrast to TGF-beta, IL-10 acted on an early step in cytokine production, its effect being maximal 3 h after addition of LPS. Unlike TGF-beta, IL-10 markedly suppressed TNF, IL-1 alpha, and IL-1 beta mRNA levels. However, this was accomplished without suppressing transcription of the corresponding genes. Moreover, cycloheximide antagonized the IL-10-dependent reduction in cytokine mRNA levels. Thus, IL-10 may induce a ribonuclease active on cytokine transcripts or may induce a protein that enhances the susceptibility of TNF, IL-1 alpha, and IL-1 beta mRNAs to ribonucleolytic action. We conclude that IL-10 and TGF-beta induce different phenotypes of macrophage deactivation, and deactivate macrophages by different mechanisms: IL-10 promotes degradation of cytokine mRNA, while TGF-beta primarily suppresses translation.
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PMID:Contrasting mechanisms for suppression of macrophage cytokine release by transforming growth factor-beta and interleukin-10. 142 77

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

Tumor necrosis factor (TNF) and interleukin-1 (IL-1) play an intimate role in the initiation and maintenance of inflammatory reactions due to their pluripotent activities. In this paper, we describe the use of an in situ hybridization analysis as an effective means to probe for TNF and IL-1 mRNA levels in primary macrophage cultures and macrophage cell lines. A significant increase in lipopolysaccharide (LPS)-induced TNF mRNA accumulation was demonstrated by in situ hybridization using either a 35S-labeled synthetic oligonucleotide (30-mer) complementary to TNF mRNA or a 35S-randomly primed labeled TNF DNA probe. An augmentation in TNF mRNA accumulation, as assessed by increasing grains/cell, was demonstrated over a wide concentration range of LPS. This accumulation was shown using both immunologically elicited primary macrophage cultures and the macrophage cell line RAW 264.7. Interestingly, the RAW 264.7 constitutively produced TNF in the absence of specific stimulus and this tonic production was observed at the molecular level via in situ hybridization analysis. Specificity of the in situ hybridization technique was shown by a complete loss in binding of 35S-probe after either RNase digestion or competition with "cold-labeled" probe. beta-actin served as a 35S-labeled control probe where the number of actin-specific grains/cell was not altered by stimulating macrophages with LPS. IL-1 alpha mRNA was also increased by LPS stimulation of macrophages as assessed by in situ hybridization. The LPS-dependent increase in macrophage mRNA for TNF and IL-1 alpha, as assessed by in situ hybridization, was confirmed by classical Northern blot analysis as well as the production of biologically-active protein.
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PMID:In situ hybridization analysis of macrophage-derived tumor necrosis factor and interleukin-1 mRNA. 326 57

Steel factor (SF), the ligand for c-kit, is an essential regulator of normal hematopoiesis, melanogenesis, gametogenesis, and mast-cell growth and development. Hematopoietic stromal cells are important sources of SF, because inactivation of SF in mice results in defects in the support function of hematopoietic stromal cells. To identify specific cells that produce, and factors that govern the expression of the different isoforms of SF in human hematopoiesis, we quantified levels of SF mRNA and membrane-bound protein in human stromal cells before and after exposure to recombinant human interleukin (IL)-1 alpha, a cytokine known to induce the expression of a variety of hematopoietic growth factors. In addition, because stromal cells in longterm bone marrow cultures (LTBMC) are supportive of hematopoietic progenitor cell survival in vitro, while umbilical vein endothelial cells (EC) and diploid fibroblasts (DF) are not, we also sought to test the hypothesis that SF gene expression would differ in cells from LTBMC when compared with EC or DF. Using reverse-transcription polymerase chain reaction amplification (RT-PCR), ribonuclease protection assays (RPA), and Northern blot analysis, SF was found to be constitutively transcribed in EC, DF, and LTBMC. IL-1 alpha neither induced accumulation of SF mRNA nor altered the ratio of exon 6+ to exon 6- transcripts in these stromal cells. By Northern blot analysis, the predominant SF mRNA species was shown to be 5.6 kb; a minor population of 3.6 kb was also found. Low levels of membrane-bound SF protein were found to be constitutively expressed by all three types of stromal cells, and were not regulated by IL-1 alpha. We conclude that the unique capacity of LTBMC to support in vitro hematopoiesis, when compared with EC or DF, cannot be explained on the basis of qualitative or quantitative differences in SF gene expression in these cells.
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PMID:Constitutive expression of steel factor gene by human stromal cells. 768 92

To investigate the mechanism by which viruses are cleared from neurons in the central nervous system, we have utilized a mouse model involving infection with a neurotropic variant of mouse hepatitis virus (OBLV60). After intranasal inoculation, OBLV60 grew preferentially in the olfactory bulbs of BALB/c mice. Using in situ hybridization, we found that viral RNA localized primarily in the outer layers of the olfactory bulb, including neurons of the mitral cell layer. Virus was cleared rapidly from the olfactory bulb between 5 and 11 days. Athymic nude mice failed to eliminate the virus, demonstrating a requirement for T lymphocytes. Immunosuppression of normal mice with cyclophosphamide also prevented clearance. Both CD4+ and CD8+ T-cell subsets were important, as depletion of either of these subsets delayed viral clearance. Gliosis and infiltrates of CD4+ and CD8+ cells were detected by immunohistochemical analysis at 6 days. The role of cytokines in clearance was investigated by using an RNase protection assay for interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, tumor necrosis factor alpha (TNF-alpha), TNF-beta, and gamma interferon (IFN-gamma). In immunocompetent mice there was upregulation of RNA for IL-1 alpha, IL-1 beta, IL-6, TNF-alpha, and IFN-gamma at the time of clearance. Nude mice had comparable increases in these cytokine messages, with the exception of IFN-gamma. Induction of major histocompatibility complex class I (MHC-I) molecules on cells in infected brains was demonstrated by immunohistochemical analyses in normal and nude mice, suggesting that IFN-gamma may not be necessary for induction of MHC-I on neural cells in vivo.
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PMID:Cytokine induction during T-cell-mediated clearance of mouse hepatitis virus from neurons in vivo. 805 31

Retinoic acid (RA), we show, induces in peripheral blood mononuclear cells a transient wave of newly transcribed, unstable interleukin-1 alpha (IL-1 alpha) and IL-1 beta mRNA. Tumor necrosis factor-alpha mRNA, by contrast, is expressed in multiple waves. IL-1 genes are primary targets for RA. Most IL-1 beta gene transcription induced by RA fails to yield mature mRNA. Instead, precursor transcripts accumulate, detected by ribonuclease protection analysis. The flow of precursors into IL-1 beta mRNA becomes inhibited during induction. When translation is blocked, e.g. by cycloheximide, expression of IL-1 beta mRNA is superinduced by 2 orders of magnitude. Superinduction is dependent on transcription, yet is unaccompanied by increased primary transcription or mRNA stability. Instead, processing of unstable IL-1 beta precursor transcripts into mature mRNA is greatly facilitated. Control is not narrowly localized within precursors: splicing of distinct exons and intron excision are enhanced by cycloheximide. Pre-mRNA processing thus is a limiting step in RA-induced IL-1 beta gene expression. This regulation is specific for RA: when induced by phorbol ester, IL-1 beta gene expression is also superinduced by cycloheximide but that response is accompanied by enhanced mRNA stability. Thus, IL-1 beta gene transcription is induced by RA, yet, unlike for other primary target genes, mRNA expression is regulated at pre-mRNA processing.
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PMID:Induction of human interleukin-1 gene expression by retinoic acid and its regulation at processing of precursor transcripts. 808 17

In this study, we have analyzed the expression and regulation of receptors for IL-2 (alpha and beta chains) and IL-4 in four lymphoid cell lines established from leukemic cells. The gibbon ape cell line MLA 144 was the only one to express constitutively the IL-2R beta chain and IL-4R, whereas the NK-like YT cells express only IL-2R beta. The two other cell lines in this study, PEER and HSB2, are derived from T lymphocytes, and express neither IL-4R, IL-2R beta, nor IL-2R alpha unless stimulated. We report here that those receptors that are constitutively expressed, i.e., IL-2R beta on YT cells and IL-2R beta or IL-4R on MLA cells, are down-regulated by stimulation with PHA + PMA. In contrast, RNase protection experiments showed that PHA + PMA stimulation of T cell lines induces mRNA for all three receptors in PEER cells, and only IL-2R alpha and IL-4R in HSB-2. Thus each of these three receptors is subjected to a different regulation, which in addition varies depending on the lineage (or differentiation stage) of the cells. This was further supported by the finding that IL-1 alpha or TNF-alpha regulates these receptors differently. These two cytokines have no effect on IL-2R beta and IL-4R in MLA and YT, but induce IL-2R alpha in YT. In contrast, they do not induce either chains of the IL-2R in the T cell lines PEER or HSB-2, but TNF induces IL-4R mRNA in HSB2 cells, and IL-1 does so in both cell lines.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of interleukin-2 and interleukin-4 receptor expression in human and ape lymphoid cell lines. 845 29

The murine MRL/lpr model of lupus nephritis is characterized by a systemic autoimmune syndrome closely resembling the human disease. The lpr mutation represents a defect in the expression of the apoptosis-signaling Fas antigen gene which causes accelerated autoimmune disease in MRL/ lpr mice and a milder, non-lethal autoimmune syndrome in C57BL6-lpr/lpr mice. The role of cytokines in autoimmune pathogenesis and its relationship with the lpr mutation remains poorly understood. In this study we utilized a RNase protection assay to quantitatively and simultaneously examine the expression of 10 different cytokine genes, namely IL-1 alpha, II-1 beta, IL-2, IL-3, IL-4, IL-5, IL-6, IFN-gamma, TNF-alpha, and TNF-beta in kidney, spleen, liver, and lymph nodes obtained from pre-diseased and diseased lupus-prone MRL/lpr, pre-diseased MRL/+2 and C57BL/6-lpr mice, as well as healthy non-autoimmune C57BL/6 and Balb/c mice. Diseased MRL/lpr mice demonstrated marked and predominant IL-1 beta gene upregulation in kidneys, liver, lymph nodes and spleen. Increased message for both TNF-alpha and IFN-gamma genes was also observed in lymph nodes, and less consistently, in the spleen, and kidneys derived from diseased MRL/lpr mice as compared to pre-diseased MRL/+2 or normal nonautoimmune control mice. Furthermore, a modest increase in the expression of both IL-1 beta and IFN-gamma message was observed in lymphoid organs of pre-diseased MRL/lpr and C57BL/6-lpr mice compared with MRL/+2 and C57BL/6 controls, respectively. Increased IL-1 beta gene expression was associated with the presence of the lpr mutation, was observed during the prediseased stage, and increased during active disease in both male and female mice. In summary, these results demonstrate that generalized up-regulation of IL-1 beta gene expression, in concert with a more limited up-regulation of both TNF-alpha and IFN-gamma expression, are prominent features of the autoimmune syndrome in the MRL/lpr model of SLE and may contribute to the disease-accelerating effect of the lpr mutation.
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PMID:Cytokine gene expression in the MRL/lpr model of lupus nephritis. 880 76

Expression of mRNA for IL-1 alpha, IL-1 beta, IL-2, IL-4, IL-5, IL-6 and TNF-alpha in inflamed gingiva was quantitatively examined by ribonuclease protection assay and in situ hybridization. The IL-1 beta mRNA expression level was statistically high (P < 0.05) in periodontitis-affected tissues compared with that in gingivitis-affected tissues. The densities of macrophages (identified as CD68-positive cells) and CD45RO-positive cells infiltrating in the inflamed gingiva correlated statistically with IL-1 beta transcript levels (macrophages, P < 0.001; CD45RO-positive cells, P < 0.002). In situ hybridization revealed IL-1 beta mRNA expression in infiltrating cells, presumed to be macrophages. The IL-1 alpha and IL-6 mRNA expression levels were much lower than the IL-1 beta transcript level, and mRNAs for IL-2, IL-4, IL-5 and TNF-alpha were negligible in these gingival tissues. The results indicate that IL-1 beta is a cytokine expressed predominantly in inflamed gingiva and reflects the density of infiltrating macrophages and other leukocytes.
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PMID:IL-1 beta mRNA as the predominant inflammatory cytokine transcript: correlation with inflammatory cell infiltration into human gingiva. 883 19


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