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)

A set of 18 plasmid subclones of the Autographa californica nuclear polyhedrosis virus genome supports expression from a late viral promoter in transient expression assays (J. W. Todd, A. L. Passarelli, and L. K. Miller, J. Virol. 69:968-974, 1995). Using this set of plasmids, we have assigned a role for each of the 18 genes required for optimal late gene expression with respect to its involvement at the levels of transcription, translation, and/or DNA replication. RNase protection analyses demonstrated that all of the known late expression factor genes (lefs) affected the steady-state level of reporter gene RNA. Thus, none of the lefs appeared to be specifically involved in translation. A subset of the lefs supported plasmid replication; ie-1, lef-1, lef-2, lef-3, p143, and p35 were essential for plasmid replication, while ie-n, lef-7, and dnapol had stimulatory effects. The predicted sequence of lef-7 suggests that it is a homolog of herpesvirus single-stranded DNA-binding protein (UL29). The role of p35 in plasmid replication appears to be suppression of apoptosis, because p35 could be functionally replaced in the replication assay by either Cp-iap or Op-iap, two heterologous baculovirus genes which suppress apoptosis by a mechanism which appears to differ from that of p35. Thus, one or more of the replication-related lefs or the process of plasmid replication appears to induce cellular apoptosis. Our results indicate that the remaining lefs, lefs 4 through 11, p47, and 39K (pp31), function either at the level of transcription or at that of mRNA stabilization.
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PMID:The roles of eighteen baculovirus late expression factor genes in transcription and DNA replication. 781 65

Pharmacological control of interleukin-12 (IL-12) production may be a key therapeutic strategy for modulating immunological diseases dominated by type-1 cytokine responses. In this study, we investigated the effects of pentoxifylline on the production of IL-12 by human blood mononuclear cells and primary human monocytes stimulated with heat-killed Staphylococcus aureus Cowan strain I (SAC) or lipopolysaccharide (LPS). Pentoxifylline potently suppressed production of IL-12 in a concentration-dependent manner. In these same experiments, tumour necrosis factor-alpha (TNF-alpha) production was inhibited and IL-10 and prostaglandin E2 (PGE2) production was enhanced by treatment with pentoxifylline. Suppression of IL-12 production by pentoxifylline was found to be independent of several known endogenous inhibitors of IL-12, such as IL-10, transforming growth factor-beta (TGF-beta), IL-4 and PGE2. RNase protection assays revealed that pentoxifylline inhibited accumulation of both IL-12 p40 and p35 mRNA, suggesting a predominant mRNA locus for pentoxifylline-induced IL-12 inhibition. Low levels of pentoxifylline added to the suppression of IL-12 production by suboptimal inhibiting doses of dexamethasone, suggesting that this drug combination may have therapeutic utility. These results provide a firm rationale for the use of pentoxifylline in clinical trials of immunological disorders characterized by inappropriate type-1 immune responses.
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PMID:Inhibition of human interleukin-12 production by pentoxifylline. 922 17

Interleukin-12 (IL-12) production by human monocytes is stringently regulated through the inducibility of both subunits, p35 and p40, and expression of p35 mRNA is the limiting factor for the secretion of the bioactive IL-12 p70 heterodimer. Optimal induction of p35 mRNA requires priming of the monocytes by interferon-gamma (IFN-gamma), followed by brief exposure to lipopolysaccharide or other bacterial products. To investigate control of p35 gene expression, we isolated genomic clones containing the human p35 gene and determined the 5' end of the mRNA expressed in monocytes. We discovered that a unique p35 transcript is induced in monocytes that begins downstream of a consensus TATA box that lies within the 5' end of the cDNA originally cloned from Epstein-Barr virus (EBV)-transformed B cells. Analysis of p35 mRNA by Northern blotting showed that the message from monocytes is approximately 200 bases shorter than message derived from the EBV-transformed B-cell line VDS. The initiation sites downstream from the TATA box were confirmed by RNase protection and 5' RACE. The data indicate that p35 transcription can initiate from different sites depending on the cell type and that the shorter inducible transcript in monocytes is the one that accumulates after stimulation. Protein translation of these two forms may result in proteins of different sizes with potential implications for the regulation of IL-12 secretion and function.
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PMID:Interferon-gamma-dependent inducible expression of the human interleukin-12 p35 gene in monocytes initiates from a TATA-containing promoter distinct from the CpG-rich promoter active in Epstein-Barr virus-transformed lymphoblastoid cells. 961 61

In order to analyze the mechanism of immuno-modulation by LPS on murine peritoneal suppressor macrophages, we have, using RNase protection assay, checked the changes of mRNA expression pattern of several cytokine genes during the immuno-modulation. It has been found that, after treating peritoneal suppressor macrophages with LPS, mRNAs of IL-12 p35, IL-12 p40, IL-6 and IFN-gamma are newly appeared, while those of IL-1 alpha, IL-1 beta and IL-1Ra are increased and those of other cytokines, like TGF-beta 1 and MIF are not changed at all. It seems certain that those cytokines, whose expression is increased by LPS stimulation, may be responsible for the functional changes of suppressor macrophages during immuno-modulation. Among these changes, the appearance of IL-12 mRNA may play a critical role, and, in this regard, the synergetic effect between IFN-gamma and LPS on the increase of IL-12 p35 and Il-12 p40 mRNA expression is an interesting finding.
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PMID:Expression of cytokine mRNA during immuno-modulation of murine suppressor macrophages. 993 40

The objective of this study was to investigate the impact of feeding mice a diet rich in n-3 polyunsaturated fatty acids (PUFA) from fish oil on the interleukin-12 (IL-12) and interferon-gamma (IFNgamma) production during the early stage of an infectious challenge with Listeria monocytogenes. Weanling female C3H/HeN mice were fed AIN-93G experimental diets containing 20%, by weight one of three fat sources: lard (low PUFA), soybean oil (n-6 PUFA) or a mixture (9:1) of menhaden fish oil and corn oil (n-3 PUFA). After 4 weeks, mice were injected intraperitoneally with 10(5) Listeria monocytogenes and the concentration of IL-12(p70) and IFNgamma in serum was determined 24 h post-infection by ELISA. IL-12p35, IL-12p40 mRNA, and IFNgamma mRNA in the spleen were quantified by RNase protection assay. The number of IFNgamma-producing cells in the spleen was determined by flow cytometry using an intracellular staining procedure. We found that n-3 PUFA-fed mice had lower levels of circulating IL-12 at 24 h post-infection than n-6 PUFA- or low PUFA-fed mice (9.7+/-3.4 pg/ml vs. 61.6+/-10.6, and 44.4+/-12.5 pg/ml, respectively; P=0.002, n = 10/trt). The level of IL-12 p35 mRNA did not significantly differ among dietary treatment groups. However, IL-12p40 mRNA was significantly lower in n-3 PUFA- and n-6 PUFA-fed mice compared to low-PUFA-fed mice. Further, the n-3 PUFA group also had the lowest circulating IFNgamma (4.4+/-1.8 ng/ml vs. 9.1+/-1.0, and 9.7+/-2.1 ng/ml, respectively; P = 0.007. n = 8-10/trt). The n-3 PUFA-fed mice had significantly lower IFNgamma mRNA in their spleens compared to the mice fed the other fat sources. In agreement with having lower circulating IFNgamma and lower splenic IFNgamma mRNA, n-3 PUFA-fed mice had a significantly lower percentage of IFNgamma-producing cells in their spleens compared with the n-6 PUFA-fed group (2.1+/-0.6 vs. 4.2+/-0.7%; P = 0.037, n = 10/trt). In summary, feeding mice a diet rich in n-3 PUFA from fish oil significantly lowered the production of both IL-12 and IFNgamma during the early phase of a Listeria infection.
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PMID:Dietary omega-3 polyunsaturated fatty acids from fish oil reduce interleukin-12 and interferon-gamma production in mice. 1006 39

Interleukin-12 (IL-12) is a monocyte/macrophage-derived cytokine that plays a prominent role in the development of T helper type 1 (Th1) cell-mediated immune responses. Glycyrrhizin (GL), an aqueous extract of liquorice root, used as Chinese medicine, is known to have various immunomodulating activities. In this study, GL showed a dose-dependent priming effect on lipopolysaccharide (LPS)-induced IL-12 p40 and IL-12 p70 (heterodimer of p40 and p35) protein production by peritoneal macrophages (PM). The maximal effect was observed when GL was intraperitoneally administered 12 hr before the PM were harvested and stimulated in vitro with LPS. The increases in IL-12 p70 and p40 protein production were primarily due to up-regulated transcription of IL-12 p35 and p40 messenger RNAs (mRNAs), as demonstrated by RNase protection assay. The augmentation of IL-12 p40 mRNA expression induced by GL pretreatment was associated with increased NF-kappaB activation. Moreover, GL exhibited the same priming effect on IL-12 production in interferon-gamma knockout (IFN-gamma-/-) mice. The production of granulocyte-macrophage colony-stimulating factor (GM-CSF) was not induced at any time point after GL pretreatment. These findings demonstrated the ability of GL to enhance LPS-induced IL-12 production by peritoneal macrophages, and indicated that the priming effect of GL on IL-12 production was independent of both IFN-gamma and GM-CSF.
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PMID:Glycyrrhizin enhances interleukin-12 production in peritoneal macrophages. 1141 11

The greatest part of nuclear C/EBPbeta (a major 35 kD protein, 30 and 38 kD isoforms) was observed to partition with the nuclear matrix. Cross-linking experiments with formaldehyde suggested that the association reflected the in situ juxtapositioning of C/EBPbeta to nuclear matrix proteins in isolated nuclei. The association of C/EBPbeta with the nuclear matrix resisted RNase and DNase treatment and extraction with protein sulfhydryl reducing agents combined with high ionic strength salt. C/EBPbeta displayed a proclivity to extensively reassemble with the filament-forming nuclear matrix proteins after a cycle of solubilization with urea, followed by its removal by dialysis. These findings suggest that the C/EBPbeta moieties were anchored to the nuclear matrix through hydrophobic protein-protein interactions with the lamins. Subsequent separation of nuclear matrix-associated C/EBPbeta into insoluble, reassembling, and soluble nuclear matrix protein (SNMP) fractions after a cycle of solubilization/reassembly pointed to the sub-partitioning of C/EBPbeta on the nuclear matrix. DNA affinity chromatography using the rat haptoglobin gene cis -element and SNMP revealed the binding of p35 during basal transcription, and p35 and p30 during elevated haptoglobin gene transcription in the course of the acute-phase (AP) response. It was concluded that the appearance of cis -element-binding p30 in the SNMP fraction resulted from its increased solubility (decreased hydrophobicity) and inability to reassociate with the lamins during urea removal. The observed solubility partitioning of C/EBPbeta on the nuclear matrix framework could represent a level of control of the general availability of regulatory proteins for establishing interactions with DNA.
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PMID:Solubility partitioning of C/EBPbeta on the rat hepatocyte nuclear matrix by hydrophobic interactions. 1209 31

A rapid multi-probe ribonuclease protection assay (RPA) was developed to quantitate equine-specific cytokine mRNA levels in activated equine monocyte-derived macrophages (EMDM) and equine peripheral blood mononuclear cells (EPBMC). Eleven template plasmids specific to 10 equine cytokine genes and the beta-actin gene were generated from which radiolabeled anti-sense RNA probes were produced. The multi-probe RPA simultaneously quantitated mRNA levels of equine IL-1alpha, IL-1beta, IL-6, IL-8, IL-10, IL-12 p35, IL-12 p40, IFN-gamma, TGF-1beta and TNF-alpha in EPBMC and EMDM with coefficients of variation as low as 0.03-0.08 (3-8%) when normalized to beta-actin expression. This sensitive and rapid assay provides a valuable tool for studies of equine immune responses.
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PMID:Simultaneous quantitation of equine cytokine mRNAs using a multi-probe ribonuclease protection assay. 1250 49

Human herpesvirus 6 (HHV-6) is a potentially immunosuppressive agent that has been suggested to act as a cofactor in the progression of HIV disease. Exposure of human macrophages to HHV-6A or HHV-6B profoundly impaired their ability to produce interleukin 12 (IL-12) upon stimulation with interferon-gamma (IFN-gamma) and lipopolysaccharide (LPS). By contrast, the production of tumor necrosis factor-alpha (TNF-alpha); regulated on activation, normal T-cell expressed and secreted (RANTES); and macrophage inflammatory protein 1 beta (MIP-1 beta) was not negatively affected. To exclude the involvement of IL-12-suppressive cytokines, such as IL-10 and TNF-alpha, the viral stocks were fractionated by ultra-centrifugation. The bulk of the suppressive activity was recovered within the virion-rich pelleted fraction that was virtually devoid of such cytokines. IL-12 suppression was independent of viral replication, and the effect was not abrogated upon ultraviolet-light inactivation of the viral inoculum. The mechanism of HHV-6-mediated IL-12 suppression was investigated by RNase protection assays, which demonstrated unaltered levels of IL-12 p35 mRNA and only a modest reduction in p40 mRNA, which was insufficient to account for the near-complete loss of both extracellular and intracellular IL-12 protein. Moreover, both the IFN-gamma and the LPS signaling pathways were intact in HHV-6-treated cells. These data suggest that HHV-6 can dramatically affect the generation of effective cellular immune responses, providing a novel potential mechanism of HHV-6-mediated immunosuppression.
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PMID:Selective suppression of IL-12 production by human herpesvirus 6. 1282

The neurodegenerative process in HIV encephalitis (HIVE) is associated with extensive damage to the dendritic and synaptic structure that often leads to cognitive impairment. Several mechanisms might be at play, including release of neurotoxins, oxidative stress and decreased activity of neurotrophic factors. Furthermore, HIV-mediated dysregulation of genes involved in neuronal maintenance might play an important role. For this purpose, cRNA was prepared from the brains of 17 AIDS patients for analysis with the Affymetrix Human U95Av2 GeneChip and analyzed with the GeneSpring Expression Analysis Software. Out of 12,625 genes analyzed, 74 were downregulated and 59 were upregulated compared to controls. Initial alternative analysis of RNA was performed by ribonuclease protection assay (RPA). In cases with HIVE, downregulated genes included neuronal molecules involved in synaptic plasticity and transmission (ion channels, synaptogyrin, synapsin II), cell cycle (p35, p39, CDC-L2, CDC42, PAK1) and signaling molecules (PI3K, Ras-Raf-MEK1), transcription factors and cytoskeletal components (MAP-1B, MAP-2, tubulin, adducin-2). Upregulated genes included those involved in neuroimmune (IgG, MHC, beta2microglobulin) and anti-viral responses (interferon-inducible molecules), transcription (STAT1, OLIG2, Pax-6) and signaling modulation (MEK3, EphB1) of the cytoskeleton (myosin, aduccin-3, radixin, dystrobrevin). Taken together, this study suggests that HIV proteins released from infected macrophages might not only induce a neuroinflammatory response, but also may promote neurodegeneration by interfering with neuronal transcription of genes involved in regulating signaling and cytoskeletal molecules important in maintaining synapto-dendritic functioning and integrity.
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PMID:Patterns of gene dysregulation in the frontal cortex of patients with HIV encephalitis. 1557 94


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