Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.26.9 (ribonuclease)
 6,589 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Granulocyte-macrophage CSF (GM-CSF) is a potent stimulator of macrophages and neutrophils and is produced by rheumatoid arthritis (RA) synovium. We now report studies that identify some of the synovial cells and cytokines responsible for local GM-CSF production and gene expression in RA. GM-CSF was assayed by ELISA in supernatants from cultured RA fibroblast-like synoviocytes stimulated with various cytokines (IL-1 beta, TNF-alpha, macrophage-CSF, IFN-gamma, IL-6, and TGF-beta). Immunoreactive GM-CSF was detected in IL-1 beta and TNF-alpha-stimulated cultures, but not in cells cultured in medium or stimulated with any of the other cytokines. IL-1 and TNF-alpha had a synergistic effect on GM-CSF production. GM-CSF gene expression by fibroblast-like synoviocytes was analyzed by ribonuclease protection assay, Northern blot analysis, and in situ hybridization. Both IL-1 beta and TNF-alpha induced GM-CSF mRNA accumulation, with a maximum effect after 4 h of stimulation. We then studied GM-CSF production by macrophage-like synoviocytes (MLS) isolated from fresh synovial specimens by flow microfluorimetry. Fresh MLS spontaneously secreted the cytokine and exogenous IL-1 beta or TNF-alpha had no effect. After 1 wk in culture, additional stimulation with IL-1 beta or TNF-alpha was required for GM-CSF production. Finally, in situ hybridization performed on freshly isolated subpopulations of synovial cells, identified GM-CSF RNA transcripts in MLS.
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PMID:Cytokines in chronic inflammatory arthritis. VI. Analysis of the synovial cells involved in granulocyte-macrophage colony-stimulating factor production and gene expression in rheumatoid arthritis and its regulation by IL-1 and tumor necrosis factor-alpha. 202 69

Lactoferrin (LF) is an iron-binding protein found in milk and other secretory fluids of mammals as well as in secondary granules of neutrophils. Receptors for LF were detected and isolated on activated T and B cells, monocytes, intestinal brush border cells, platelets and neoplastic cells. Very low physiologic serum levels of LF increase significantly upon infection. Serum concentration of LF is also elevated in rheumatoid patients. It is suggested that the ability of LF to bind an excess of Fe() ions, needed for growth of microorganisms and tumors, represents an important defence mechanism in humans. LF, in addition, may contribute to the protection against pathogens and their metabolites by enhancing phagocytosis, cell adherence and controlling release of proinflammatory cytokines such as IL-1, IL-6 and TNF-alpha. The protein diminishes also damaging effects of free radical release. LF possesses interesting immunotropic properties with regard to immature T and B cells by promoting phenotypic and functional maturation of these cells. LF also controls the effector phase of cellular immune response and inhibits manifestations of autoimmune response in mice. One molecular form of LF with a ribonuclease activity may have a prognostic value in breast cancer. Lactoferrin may be potentially applied in neutropenic patients or in patients with bleeding disorders as a preoperative immunomodulator.
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PMID:[Lactoferrin--its role in defense against infection and immunotropic properties]. 877 12

During the Spacelab Life Sciences-2 mission, rats were dissected in space and biosamples were returned to Earth for analysis. Immunologic studies addressed the kinetics of T lymphocyte proliferative responses, cytotoxic activity of natural killer cells, and cytokine production. Experiments were performed by using spleen and bone marrow of rats dissected before flight, during flight, immediately after landing of the space shuttle (R + 0), or 14 days after landing (R + 14), as well as those of respective control animals. Each group consisted of five male Sprague-Dawley rats. It was demonstrated that T lymphocyte activity of rats dissected in flight was significantly decreased compared with the controls. This was observed during 48-, 72-, and 96-h cultivation and stimulation with the following mitogenic stimuli: concanavalin A (Con A; 0.1, 1.0, and 10.0 mg/ml), phytohemagglutinin (PHA; 2.5 mg/ml), and interleukin-2 (IL-2; 1 U/ml). The cell proliferation rate in rats dissected immediately after landing did not decrease, whereas that in rats dissected at R + 14 increased. The activity of spleen natural killer cells was reduced in response to 51Cr-labeled target cells during flight (YAC-1 and K-562) and after flight (YAC-1). At R + 14, their activity returned to normal. Another technique employed to measure natural cytotoxicity, using [3H]uridine-labeled target cells and ribonuclease, did not reveal any differences between control and experimental groups. In bone marrow, the activity of natural killer cells did not vary significantly. The production of IL-1, IL-2, tumor necrosis factor (TNF)-alpha, and TNF-beta in spleen cell cultures of the flight rats was reduced. At R + 0, IL-1 and TNF-beta levels remained lowered, whereas TNF-alpha was increased. At R + 0, interferon-alpha and interferon-gamma levels were diminished. In summary, cell-mediated immunity in rats was significantly suppressed during flight. The time course variation of immune parameters after flight suggests that the changes may truly indicate a response of the immune system to spaceflight conditions that could increase over time.
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PMID:Effect of SLS-2 spaceflight on immunologic parameters of rats. 882 61

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

Recent studies indicate that a peroxisome proliferator-activated receptor, PPAR gamma, functions as an important adipocyte determination factor. In contrast, tumor necrosis factor-alpha (TNF alpha) inhibits adipogenesis, causes dedifferentiation of mature adipocytes, and reduces the expression of several adipocyte-specific genes. Here, we report that treatment of 3T3-L1 adipocytes with TNF alpha resulted in a time- and concentration-dependent decrease in PPAR gamma mRNA expression to the level detected in preadipocytes. PPAR gamma mRNA levels were reduced by 95% with 3 nM TNF alpha treatment for 24 h. Half-maximal effects were seen after 3 h treatment with 3 nM TNF alpha or with 50 pM TNF alpha (24-h exposure). Parallel reductions in PPAR gamma protein levels were also observed after treatment of 3T3-L1 adipocytes with TNF alpha. Using a ribonuclease protection assay, both alternatively spliced PPAR gamma isoforms (gamma 1 and gamma 2) were shown to be negatively regulated by TNF alpha. The down-regulation of PPAR gamma by TNF-alpha preceded the diminution in expression of other adipocyte-specific genes including CCAAT/enhancer binding protein and adipocyte fatty acid-binding protein (aP2). The effect of TNF alpha was specific for the gamma-isoform of PPARs, since the expression of PPAR delta mRNA was not affected by treatment with TNF alpha. Low level constitutive expression of PPAR gamma in 3T3-L1 adipocytes (at levels approximately 2- to 3-fold higher than in preadipocytes) partially blocked the inhibitory effect of TNF alpha on aP2 and adipsin expression. These findings support the following conclusions: 1) PPAR gamma expression is necessary for the maintenance of the adipocyte phenotype. 2) PPAR gamma, but not PPAR delta, expression is sufficient to attenuate TNF alpha-mediated effects on adipocyte phenotype. 3) Reduced PPAR gamma gene expression is likely to represent an important component of the mechanism by which TNF alpha exerts its antiadipogenic effects.
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PMID:Negative regulation of peroxisome proliferator-activated receptor-gamma gene expression contributes to the antiadipogenic effects of tumor necrosis factor-alpha. 892 70

To define the potential role of interleukin-6 (IL-6) and its soluble receptor alpha in cartilage metabolism, we analyzed their effects on tissue inhibitor of metalloproteases (TIMP) synthesis by synoviocytes and chondrocytes. TIMP-1 production by isolated human articular synovial fibroblasts and chondrocytes, stimulated by IL-6 and/or its soluble receptor, was first assayed by specific enzyme-linked immunosorbent assay; the slight stimulatory effect of IL-6 on TIMP-1 production by both types of cells was markedly amplified by the addition of soluble receptor, the maximal secretion being observed only at 96 h. TIMP-1 mRNA expression, determined by ribonuclease protection assay, was induced by IL-6 together with its soluble receptor, but TIMP-2 and -3 mRNAs were not affected by these factors. A specific neutralizing antibody abolished the effects of the soluble receptor. Finally, supernatant from synoviocytes stimulated by IL-6 plus its soluble receptor blocked almost completely the collagenolytic activity of supernatant from IL-1-induced synoviocytes. These observations indicate that IL-6 and its soluble receptor have a protective role in the metabolism of cartilage. Given the high levels of soluble receptor in synovial fluid and the marked induction of IL-6 by IL-1 or TNF-alpha, it is likely that IL-6 and its soluble receptor are critical in controlling the catabolic effects of pro-inflammatory cytokines.
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PMID:Interleukin (IL)-6 and its soluble receptor induce TIMP-1 expression in synoviocytes and chondrocytes, and block IL-1-induced collagenolytic activity. 959

Onconase (ONC) a ribonuclease from amphibian oocytes is cytostatic and cytotoxic to many human tumor lines, shows in vivo antitumor activity in mouse tumor models and is in Phase III clinical trials. The mechanism of antitumor activity of ONC is presumed to be due to its internalization, degradation of intracellular RNA and suppression of protein synthesis. Since apoptosis triggered by TNF-alpha is known to be potentiated by inhibitors of protein synthesis, we have hypothesized that it also may be potentiated by ONC. Indeed, preincubation of U-937 or HL-60 leukemic cells with 0.17 microM ONC rendered them more sensitive to induction of apoptosis by TNF-alpha or antibody to CD95 (Fas). The mechanism by which ONC amplifies the effect of TNF-alpha may involve suppression of induction of the survival genes whose expression is triggered by activation of NFkB by this factor.
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PMID:Potentiation of tumor necrosis factor induced apoptosis by onconase. 962 97

Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that function in the turnover of extracellular matrix components during development. In addition, MMPs also contribute to pathological conditions associated with inflammation, angiogenesis, and tumor invasion. A 72-kDa type IV collagenase, also referred to as gelatinase A or MMP-2, has been proposed to potentiate the invasion and metastasis of malignant tumors. In particular, MMP-2 activity has been shown to constitute an important component of human astroglioma invasion. We investigated the influence of various cytokines, both proinflammatory and immunosuppressive, on MMP-2 gene expression in two human astroglioma cell lines (U251-MG and CRT). Our results indicate that the cell lines constitutively express high levels of MMP-2 mRNA, protein, and bioactivity as assessed by ribonuclease protection assay, immunoblotting, and zymography assays, respectively. The proinflammatory cytokines TNF-alpha and IFN-gamma individually can inhibit constitutive MMP-2 expression, and function in an additive manner for near-complete inhibition of MMP-2 expression. Inhibition of MMP-2 mRNA levels by TNF-alpha and IFN-gamma is not due to destabilization of the MMP-2 message; rather, inhibition is mediated at the transcriptional level. Furthermore, TNF-alpha/IFN-gamma inhibition of MMP-2 expression results in decreased invasiveness of the human astroglioma cells through an extracellular matrix. These results raise the possibility that TNF-alpha and IFN-gamma may have beneficial effects in attenuating astroglioma invasive properties.
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PMID:Transcriptional suppression of matrix metalloproteinase-2 gene expression in human astroglioma cells by TNF-alpha and IFN-gamma. 986 95

We examined the potential of several epithelial-derived factors to enhance neutrophil activation and survival. Neutrophils incubated in the presence of supernatants from nasal-derived primary epithelial cultures had significantly increased survival compared with neutrophils cultured in media alone. Of the cytokines reported to enhance neutrophil survival, transcripts for interleukin (IL)-1alpha, IL-1beta, IL-6, and granulocyte macrophage colony-stimulating factor (GM-CSF) (but not interferon-gamma or granulocyte colony-stimulating factor [G-CSF]) were detected by ribonuclease protection assay in basal and tumor necrosis factor (TNF)-alpha- stimulated epithelial cells. Of the eicosanoid products that enhance neutrophil survival, platelet-activating factor and leukotriene B(4) were not detected in the supernatants, whereas prostaglandin E(2) (PGE(2)) was produced in modest amounts. The levels of IL-6, GM-CSF, and PGE(2) in epithelial supernatants were significantly increased after transient TNF-alpha stimulation. This induction was suppressed if dexamethasone (Dex) was added during TNF-alpha stimulation. Only IL-6, GM-CSF, and PGE(2) promoted neutrophil survival over the range of concentrations detected in the supernatants, and a combination of neutralizing antibodies to GM-CSF and IL-6 completely inhibited the enhanced neutrophil survival in epithelial supernatants. Both the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling technique and morphologic scoring of apoptotic neutrophils confirmed that epithelial supernatants, as well as purified IL-6, GM-CSF, and PGE(2) all delayed neutrophil apoptosis. Finally, the effects of Dex on neutrophil survival and on epithelial cytokine production were investigated. Dex independently prolonged neutrophil survival but suppressed epithelial production of survival-enhancing factors in a dose-dependent manner. The net effect of Dex appeared to favor neutrophil survival.
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PMID:Multiple epithelial cell-derived factors enhance neutrophil survival. Regulation by glucocorticoids and tumor necrosis factor-alpha. 1042 10

Tumor necrosis factor (TNF) receptor (TNFR)-associated factors 1 and 2 (TRAF1 and TRAF2) and inhibitor of apoptosis proteins cIAP1 (MIHB) and cIAP2 (MIHC) were recently identified as proteins that associate with the TNF-alpha receptors TNFRI (p55) and TNFRII (p75) and inhibit TNF-alpha-induced programmed cell death or apoptosis. In the original reports, TRAF1 expression, unlike the ubiquitous TRAF2, was restricted to specific tissues in the lung, spleen, and testis. TNF-alpha is increased in the lung in many forms of pulmonary disease. In the current study, Western analysis, immunohistochemistry, and ribonuclease protection assays were used to determine whether TNF-alpha regulates the expression of these TNFR-associated proteins in lung cells. We demonstrate for the first time TNF-alpha dose-dependent induction of TRAF1 protein and messenger RNA (mRNA) in human H441 and A549 pulmonary adenocarcinoma cell lines, as well as in lung cells of C57BL/6J mice after intratracheal administration of TNF-alpha. In contrast to the epithelial cells, TRAF1 was not induced by TNF-alpha in U937 cells, a human monocytic cell line, suggesting cell type-specific regulation. Similarly, cIAP2 mRNA was induced by TNF-alpha in both H441 and A549 pulmonary epithelial cells but not in U937 cells. TNF-alpha is a primary mediator of acute pulmonary inflammation and contributes to the pathophysiology of chronic lung diseases such as bronchopulmonary dysplasia (BPD), a fibrotic disease of prematurely born infants. Immunohistochemical staining of human neonatal lung tissue demonstrated increased TRAF1 in lungs of infants dying of pneumonia or BPD in comparison with those dying of congenital malformation. These studies support the hypothesis that the TRAF1 and cIAP2 genes are highly regulated in pulmonary cells and may play a role in human lung disease.
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PMID:Tumor necrosis factor-alpha-induced lung cell expression of antiapoptotic genes TRAF1 and cIAP2. 1065 35


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