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:2.7.7.6 (RNA polymerase)
34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Peripheral lymphoid tissues contain a fibroblastic cell type referred to as stromal cells or reticulum cells which interact with lymphocytes as part of the lymphoid microenvironment. After isolation from human tonsils and expansion in vitro we analyzed the surface phenotype, extracellular matrix components, cytoskeletal products, cytokine production, binding and functional interaction with B lymphocytes of in vitro cultured stromal cells (HTSC) both in resting condition and after activation with tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma. Our results show that HTSC do not express specific myeloid, lymphoid, endothelial or epithelial markers. HTSC express CD54 (ICAM-1), CD49a (VLA-1), CD49b (VLA-2), CD49c (VLA-3), CD49e (VLA-5), CD49f (VLA-6), CD29, CD51, CD44 and produce vinculin, beta-tubulin, alpha-actin, vimentin, fibronectin, laminin and collagen types I, III and IV. Activation of HTSC up-regulated CD54 (ICAM-1) and induced HLA-DR and CD106 (VCAM-1). HTSC constitutively produce interleukin (IL)-6 which is enhanced upon activation with TNF-alpha. IL-8 and granulocyte/macrophage colony-stimulating factor are detected only in the supernatants of activated HTSC. Reverse transcriptase polymerase chain reaction analysis revealed that HTSC display mRNA for IL-1 alpha, leukemia inhibitory factor and IL-7. The adhesion of tonsillar B lymphocytes to activated HTSC is mediated by CD11a/CD18 and CD54. Furthermore, HTSC can induce maximal proliferation of IL-2-activated B lymphocytes cocultured in direct cell-cell contact with HTSC. These results clearly distinguish in vitro cultured HTSC from common fibroblasts and other non-lymphoid elements present in the lymphoid parenchyma, such as follicular dendritic cells, and show that HTSC actively participate in the lymphoid microenvironment. In vitro cultures of HTSC could therefore be a useful model system for detailed analysis of the interactions between stromal cells and lymphocytes under physiological and pathological conditions.
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PMID:In vitro cultured stromal cells from human tonsils display a distinct phenotype and induce B cell adhesion and proliferation. 856 62

Recent reports describe the beneficial use of alpha interferon (IFNalpha) for the treatment of idiopathic hypereosinophilic syndrome (HES) unresponsive to conventional therapy. A clinical improvement associated with a rapid decrease of peripheral blood eosinophilia suggested possible direct effects of IFNalpha on eosinophils through the presence of IFNalpha receptors (IFNalphaR). Reverse transcriptase-polymerase chain reaction (RT-PCR) and cytochemistry were used respectively to detect the presence and define the distribution of IFNalphaR on enriched eosinophil preparations purified from blood cells. IFNalphaR was found on eosinophils collected from patients with various eosinophilic disorders. In addition, IFNalpha inhibited the release of eosinophil granule proteins such as eosinophil cationic protein (ECP), neurotoxin (EDN, or interleukin-5 (IL-5). Moreover, antiparasite cytotoxicity was also strongly reduced in a dose-dependent manner by IFNalpha. These results provide the first evidence that human eosinophils express a functional receptor for IFNalpha and represent a potential basis for the beneficial effects of IFNalpha in patients with hypereosinophilic syndromes.
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PMID:Eosinophils express a functional receptor for interferon alpha: inhibitory role of interferon alpha on the release of mediators. 863 Mar 98

The adhesion molecule intercellular adhesion molecule-1 (ICAM-1), in addition to its membrane-associated form (mICAM-1), also exists as a soluble form (sICAM-1). sICAM-1 is capable of binding to lymphocyte function associated antigen-1 (LFA-1) molecules, and production of sICAM-1 is therefore thought to have immunomodulatory consequences. The present study, which employed normal human keratinocytes as a model for sICAM-1-producing cells, was conducted to determine the mechanism responsible for the production of sICAM-1 and to develop a strategy for specific inhibition of sICAM-1 production. Stimulation of keratinocytes with recombinant human gamma-interferon (rhIFN-gamma) induced both expression of mICAM-1 and production of sICAM-1. Western blot analysis revealed that keratinocyte-derived sICAM-1, compared to mICAM-1, had a smaller molecular size, approximately a 7-kD difference. Neither by Northern blot analysis nor by reverse-transcriptase polymerase chain reaction (RT-PCR) was any evidence for alternatively spliced ICAM-1 mRNA obtained. Addition of the protease inhibitors iodoacetamide and E-64, however, inhibited the production of sICAM-1 in a dose-dependent manner. The involvement of proteolytic cleavage in the production of sICAM-1 was corroborated in minimal peptide protection assays, in which minimal peptides covering the potential cleavage site of ICAM-1 were added to sICAM-1-producing keratinocytes. One of these peptides, ICAM cleavage inhibitory peptide (ICAM-CIP), inhibited the production of sICAM-1 without affecting mICAM-1 expression. These studies demonstrate that sICAM-1 production in human keratinocytes is due to proteolytic cleavage, and that the oligopeptide ICAM-CIP may specifically inhibit this mechanism. The capacity of ICAM-CIP to selectively prevent production of sICAM-1 may be useful for the development of novel therapeutic approaches relevant for the management of inflammation and cancer.
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PMID:Analysis of the production of soluble ICAM-1 molecules by human cells. 864 65

Hepatitis C virus (HCV) is an enveloped, single-stranded RNA virus that has been classified in the Flaviviridae family. The genome of 9400 nucleotides comprises two non-coding regions in 5' and 3' flanking a large reading frame which codes for a polyprotein of 3000 amino acids; this polyprotein is further cleaved into structural (C, E1, E2) and non-structural (NS1, NS2, NS3, NS4, NS5) proteins. The positive RNA acts as a cap-independent messenger; the transcription is mediated by the NS5 RNA polymerase. After the maturation step, the virion is liberated by budding through the cytoplasmic membrane. As for many other RNA viruses, the HCV genome exhibits a high degree of variability, especially in the E2/NS1, E1, NS3 and NS5b regions. Conversely the 5' non-coding region is highly conserved, at least in part, and can be used for diagnostic purposes by PCR technique. Six genotypes of HCV have already been reported, numbered from 1 to 6 in Simmonds' classification. The same genotype can be divided into subtypes (for instance, genotype 1 comprises three subtypes: 1a, 1b and 1c). Various minor variants of the same strain, called quasispecies, are commonly present in the blood of the same patient. Strains of genotype 1b--which is the most widespread worldwide--are correlated with more severe clinical manifestations, greater viral loads and lower response to interferon treatment. The high variability of the HCV genome contributes greatly to the difficulty of designing potent vaccines.
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PMID:Structure, genomic organization, replication and variability of hepatitis C virus. 891 41

The relative levels of selected cytokine, interleukin-2 receptor, class II DR and DQ RNAs, and maedi visna virus (MVV) RNA were measured by reverse-transcriptase polymerase chain reaction (RT-PCR) in the lungs of sheep with natural maedi visna virus infection (n = 8) and a group of age/sex/breed-matched MVV seronegative sheep (n = 4). These animals were divided into two groups, irrespective of serostatus, according to the severity of lymphocytic interstitial pneumonia. The severity of lung lesions was determined by clinical sign, lung weight, and lesion sore in the lungs measured by three pathologic parameters. Sheep with lung lesions showed hyperelevated levels of granulocyte-macrophage colony-stimulating factor upregulated gamma-interferon, interleukin 2 receptor, and interleukins 1 beta, 4, and 10 mRNAs. Class II mRNAs were found not to be elevated in the lungs of sheep with lung lesions. Tumor necrosis factor alpha and transforming growth factor beta 1 mRNA levels were similar in all sheep lungs studied. We discuss the major roles played by granulocyte-macrophage colony-stimulating factor and type 2 cytokines in the pathogenesis of this disease and the possible stimulation of the production of these cytokines by viral surface glycoproteins.
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PMID:Differential levels of mRNAs for cytokines, the interleukin-2 receptor and class II DR/DQ genes in ovine interstitial pneumonia induced by maedi visna virus infection. 916 76

We recently found that complement C3 is locally synthesized and secreted into the exocrine pancreas. In the present study, we attempted to demonstrate the secretion of complement C4 and factor B in the exocrine pancreas. In five samples of pancreatic fluid, both C4 and factor B proteins were detected by enzyme-linked immunosorbent assay (ELISA). Immunoblot analysis revealed the C4 and factor B molecules in pancreatic fluid to be identical with these molecules in serum. Reverse transcriptase (RT)-polymerase chain reaction (PCR) analysis in pancreatic carcinoma cell lines suggested ductal epithelial cells to be the local production sites of these proteins in the pancreas. The secretion of C4 and factor B in ductal cell lines (PANC-1 and MIA PaCa-2) was independently regulated by interleukin (IL)-1 beta, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma; C4 secretion was induced by IFN-gamma, whereas factor B secretion was induced by IL-1 beta, TNF-alpha, or IFN-gamma. These observations indicate that: (a) complement C4 and factor B are secreted into the exocrine pancreas, (b) ductal epithelial cells appear to be the site of C4 and factor B biosynthesis, and (c) local secretion of C4 and factor B in the pancreas is differentially regulated by IL-1 beta, TNF-alpha, and IFN-gamma.
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PMID:Biosynthesis and secretion of MHC class III gene products (complement C4 and factor B) in the exocrine pancreas. 921 52

Because current standard therapy of chronic hepatitis C with alpha interferon is less than ideal, numerous other approaches have been studied. Iron in the liver, particularly that found in vascular endothelial cells of portal tracts, has been associated with decreased responsiveness to alpha interferon therapy. Iron reduction alone, generally achieved by therapeutic phlebotomy, regularly has been associated with biochemical improvement (decrease in serum alanine aminotransferase), but not with virological improvement. Iron reduction has been reported to increase the therapeutic response to alpha interferon. Most studies of this combination have been conducted in patients who had not responded to interferon alone; in these patients, improved responsiveness has been observed in some, but not all studies. In patients not previously treated, iron reduction was found in a recent trial to improve the sustained biochemical and virological response rate from 5% to 29%. Hepatic iron and chronic hepatitis C increase oxidative stress in the liver and are associated with decreases in hepatic glutathione levels. In one report, administration of N-acetyl cysteine, a sulfhydryl donor, led to improved response to interferon in chronic hepatitis C. Several cytokines and immunomodulators have undergone limited study; perhaps the most promising of these is thymosin alpha-1. In one small study, amantadine was found to produce some response in patients who previously had failed to respond to interferon. Ursodiol improves serum aminotransferase levels in chronic hepatitis C but has no antiviral effect, nor has it been found to improve histologic abnormalities. The future of therapy of chronic hepatitis C will likely include measures to decrease oxidative stress and injury and multidrug combinations, including inhibitors of the hepatitis C viral protease and RNA polymerase.
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PMID:Therapy of hepatitis C: other options. 930 80

The incidence of malignant melanoma continues to rise steadily in the United States, with approximately 40,300 new cases expected in 1997. A significant number of patients with deep primary lesions or regional lymph node metastases are at high risk for developing recurrent, metastatic disease despite adequate surgical intervention. Therefore, approaches to adjuvant therapy including immunotherapy, such as interferon, levamisole, and vaccines and chemotherapy and chemoimmunotherapy have been investigated in high-risk patients. The key adjuvant trials are reviewed, with emphasis placed on randomized trials. High-dose interferon-alpha has recently been shown to modestly improve disease-free and overall survival in a prospective randomized trial of high-risk patients and has been approved by the FDA for this indication. Vaccines, which currently remain experimental, may prove to be equally effective but less toxic options for adjuvant therapy. Also, the identification of more high-risk patients who might benefit from adjuvant therapy may be facilitated by sentinel lymph node biopsy and the reverse-transcriptase polymerase chain reaction for tyrosinase.
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PMID:Adjuvant therapy of malignant melanoma. 930 94

The aim of this study was to compare the short-term and long-term efficacy and safety of lymphoblastoid interferon with a recombinant interferon alfa (IFN-alpha) in a 24-week treatment course for chronic hepatitis C. One thousand seventy-one patients with chronic hepatitis C were randomized to receive lymphoblastoid IFN-alpha n1 or recombinant IFN-alpha2b at the same dosing regimen, 3 million units administered subcutaneously three times a week for 24 weeks. Hepatitis C viral (HCV) genotype (by line probe assay) was determined at baseline, and serum HCV RNA level (by quantitative reverse-transcriptase polymerase chain reaction) was measured at baseline and weeks 24, 48, and 72. Primary end points were normalization of serum alanine aminotransferase (ALT) levels at end of therapy (week 24) and sustained ALT normalization at weeks 48 and 72. Secondary end points were nondetectability of serum HCV RNA at 24, 48, and 72 weeks, and histological improvement at weeks 24 and 72. The two treatment groups were similar with respect to demographic, clinical, and histological variables (10% had cirrhosis at entry), baseline serum HCV RNA levels, and distribution of HCV genotypes. Intent-to-treat analysis showed that ALT response at end of treatment was 35.3% for IFN-alpha n1 and 37.9% for IFN-alpha2b (P = .38). Histological improvement and nondetectability of HCV RNA were also similar between the two treatment groups at the end of treatment, as were the type and frequency of reported adverse experiences. Among treatment responders, post-treatment relapse was significantly less frequent with IFN-alpha n1 than with IFN-alpha2b. Thus, sustained ALT responses (SR) to IFN-alpha n1 were significantly more frequent than SR to IFN-alpha2b (12.0% vs. 7.6% at 48 weeks, P = .02; 10.3% vs. 6.7% at 72 weeks, P = .04). SR were associated with viral loss and histological improvement, and more patients treated with IFN-alpha n1 were HCV RNA negative at week 72 compared with patients treated with IFN-alpha2b (P = .03). SR at week 72 were two- to sixfold better with other HCV genotypes relative to type 1, but the improved long-term efficacy of IFN-alpha n1 compared with IFN-alpha2b was evident for all major HCV genotypes. It is concluded that IFN-alpha n1 and IFN-alpha2b have similar end-of-treatment response rates and safety profiles but the sustained response rate is higher with IFN-alpha n1. SR to IFN-alpha treatment are associated with clearance of HCV RNA, and histological improvement was maximal in patients who exhibited sustained ALT normalization and clearance of HCV RNA.
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PMID:Lymphoblastoid interferon alfa-n1 improves the long-term response to a 6-month course of treatment in chronic hepatitis C compared with recombinant interferon alfa-2b: results of an international randomized controlled trial. Clinical Advisory Group for the Hepatitis C Comparative Study. 953 53

We examined the effects of infectious bursal disease virus (IBDV) on splenic T cells and macrophages. In acute IBDV infection, splenocytes responded poorly to Con A stimulation. However, when T cells were isolated from whole spleen cells, purified T cells responded normally to Con A. This result indicated that functional T cells were present in the spleen but mitogen-induced proliferation of T cells was being suppressed by other cells. Previous studies indicated that soluble factors from suppressor cells may mediate this inhibition of T cell mitogenesis. We thus examined the effects of IBDV on spleen adherent cells. Reverse transcriptase-polymerase chain reaction (RT-PCR) was used to quantitate the expression of several cytokine genes in splenic macrophages. In acute IBDV infection, splenic macrophages exhibited enhanced gene expression of type I interferon (IFN), chicken myelomonocytic growth factor (cMGF), an avian homolog of mammalian IL-6, and 9E3/CEF4, an avian homolog of mammalian IL-8. Mitogen-stimulated spleen cell cultures also produced elevated levels of nitric oxide. The elevation of cytokine gene expression by macrophages occurred transiently during the acute phase of viral infection and coincided with in vitro inhibition of T cell mitogenic response of spleen cells.
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PMID:Enhanced expression of cytokine genes in spleen macrophages during acute infection with infectious bursal disease virus in chickens. 961 45


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