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)

Oligodendrocytes in multiple sclerosis brain may be under a direct attack by proinflammatory cytokines, particularly tumor necrosis factor-alpha (TNFalpha) and interferon-gamma (IFNgamma). In this study, we have examined the in vitro cytotoxic effects of the two cytokines, individually and in combination, on oligodendrocyte lineage cells using morphological criteria, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide reduction assay (MTT), terminal deoxynucleotide transferase-mediated dUTP nick end-labeling (TUNEL), and agarose-gel electrophoretic analysis of fragmented DNA. IFNgamma exerted a dose-dependent cytotoxic effect on cultured CG4 cells, an oligodendrocyte progenitor cell line, and in primary cultures of purified oligodendrocyte progenitors. TNFalpha, while by itself being only mildly toxic, greatly potentiated the cytotoxicity of IFNgamma. The cytokine effects were developmentally modified in that their cytotoxic and cooperative effects became less evident in more differentiated cells. A cell-permeable peptide inhibitor (i.e., z-VAD.fmk) of caspases partially suppressed apoptotic changes elicited by the cytokine combination in CG4 cells but not in primary oligodendrocytes. Reverse transcriptase polymerase chain reaction (RT-PCR) analysis of mRNA prepared from cytokine-treated cultures revealed an increased expression of the death receptor, Fas. The results suggest particular vulnerability of oligodendrocyte progenitors to a combination of TNFalpha and IFNgamma involving an activation of the cell death program.
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PMID:TNFalpha potentiates IFNgamma-induced cell death in oligodendrocyte progenitors. 984 48

A new phthalimido compound, N-[2-(2-phthalimidoethoxy)acetyl]-L-alanyl-D-glutamic acid (CAS 142489-47-2, LK423), was examined along with other N-acyl-desmuramyldipeptide compounds for possible immunomodulating activities in cyclophosphamide (Cy)-treated mice. Reverse transcriptase-polymerase chain reaction (RT-PCR) and Northern blot assays demonstrated that multiple subcutaneous injections of LK423 (1 to 50 micrograms/days, for 4 days) into these mice resulted in upregulating interleukin-10 (IL-10) gene expression in the spleen. In contrast to IL-10, expression of interferon-gamma (IFN-gamma) gene was reduced by treating with this compound. The culture supernatant of spleen cells obtained from the mice that had received LK423 injections was found to contain a larger amount of IL-10 protein than in the culture supernatant of the spleen obtained from the mice that received no LK423 injections when tested by enzyme-linked immunosorbent assay (ELISA). Conversely to IL-10, the concentration of IFN-gamma was lower in the culture supernatant from the LK423-treated group than that in the control group. In contrast to this compound, other N-acyl-desmuramyldipeptide derivatives carrying a L-alanyl-D-isoglutamine moiety, and other immunological stimulants showed an activity to augment production of IFN-gamma and reduce the gene expression of IL-10. The immunological activities of this new phthalimido desmuramyldipeptide compound, LK423, are discussed from the point of view of its therapeutic application.
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PMID:Interleukin-10 inducing activity of LK423, a phthalimido-desmuramyldipeptide compound. 1002 84

Bone marrow-culture-derived macrophages activated with interferon-gamma and lipopolysaccharide produced less nitric oxide (NO) when cultured with vesicular stomatitis virus (VSV)-infected BALB/c3T3 (3T3-VSV) than macrophages activated in an identical manner and cultured alone, with uninfected BALB/c3T3 (3T3), or with P815. However, all four groups of macrophages produced nearly the same amount of interleukin-6 (IL-6). Addition of VSV to activated macrophages did not change the amount of NO produced. The amount of NO generated by two non-macrophage sources of NO was not affected by the presence of either P815 or 3T3-VSV. Reverse transcriptase-polymerase chain reaction showed a decrease in the amount of inducible nitric oxide synthase (iNOS) but not IL-6 mRNA from macrophages cocultured with 3T3-VSV compared with macrophages cocultured with P815. The reduction in iNOS mRNA was confirmed by ribonuclease protection assay. When RAW 264.7 transfected with an iNOS regulatory construct were activated and incubated with 3T3-VSV there was a decrease in the expression of the reporter luciferase gene and NO production but not IL-6 production compared with cells incubated with either medium alone or with P815.
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PMID:Interaction with vesicular stomatitis virus-infected BALB/c3T3 cells inhibits the synthesis of nitric oxide in activated murine bone marrow culture-derived macrophages. 1033 88

Although possessing a morphologically similar small bowel abnormality to patients with isolated gluten-sensitive enteropathy (GSE), patients with dermatitis herpetiformis (DH) have few gastrointestinal symptoms and exhibit blistering skin lesions and cutaneous IgA deposits. To determine whether clinical discrepancies between these gluten-sensitive conditions might be the result of different patterns of small bowel cytokine expression, duodenal biopsies were obtained from eight DH patients and nine isolated GSE patients. Biopsies were evaluated for interleukin-4 (IL-4) and interferon-gamma (IFN-gamma) expression by reverse-transcriptase polymerase chain reaction (message) and immunohistochemistry (protein). In DH patients, most of whom had no gut symptoms, IFN-gamma mRNA expression was significantly less than in isolated GSE patients with symptomatic gut disease. Conversely, IL-4 mRNA expression in DH patients was greater than that found among isolated GSE patients. These findings suggest that the different clinical phenotypes of gluten sensitivity may be caused by variation in cytokine expression in the small bowel response to gluten.
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PMID:Expression of interleukin-4 and interferon-gamma in the small bowel of patients with dermatitis herpetiformis and isolated gluten-sensitive enteropathy. 1054 67

Erythema multiforme follows administration of several drugs or infection with various agents, including herpes simplex virus, a syndrome designated herpes simplex virus associated erythema multiforme. Lesional skin from 21 of 26 (81%) herpes simplex virus associated erythema multiforme patients was positive for herpes simplex virus gene expression as evidenced by reverse transcriptase-polymerase chain reaction with primers for DNA polymerase and/or immunohistochemistry with DNA polymerase antibody. Reverse transcriptase-polymerase chain reaction and immunohistochemistry studies indicated that herpes simplex virus associated erythema multiforme lesional skin from 16 of 21 (76%) DNA polymerase positive herpes simplex virus associated erythema multiforme patients was also positive for interferon-gamma, a product of T cells involved in delayed-type hypersensitivity (p < 0. 0001 by Pearson correlation coefficient). Interferon-gamma signals were in infiltrating mononuclear cells and in intercellular spaces within inflammatory sites in the epidermis and at the epidermis/dermis junction. Herpes simplex virus lesional skin was also positive for DNA polymerase [five of five (100%)] and interferon-gamma [four of five (80%)], but lesional skin from drug-induced erythema multiforme patients was negative. Lesional herpes simplex virus associated erythema multiforme keratinocytes also stained with antibody to transforming growth factor-beta [14 of 23 (61%)] and cyclin-dependent kinase inhibitor waf [12 of 18 (67%)]. Staining was also seen in keratinocytes from herpes simplex virus lesions [five of five (100%)], but not in normal skin. By contrast, staining with antibody to tumor necrosis factor-alpha, another pro-inflammatory cytokine, was seen in seven of 11 (64%) drug-induced erythema multiforme patients, but not in herpes simplex virus or herpes simplex virus associated erythema multiforme patients, and lesional keratinocytes from drug-induced erythema multiforme patients were negative for transforming growth factor-beta and cyclin-dependent kinase inhibitor waf. We interpret the data to indicate that herpes simplex virus associated erythema multiforme pathology includes a delayed-type hypersensitivity component and is mechanistically distinct from drug-induced erythema multiforme.
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PMID:Herpes simplex virus associated erythema multiforme (HAEM) is mechanistically distinct from drug-induced erythema multiforme: interferon-gamma is expressed in HAEM lesions and tumor necrosis factor-alpha in drug-induced erythema multiforme lesions. 1057 38

B-cell lymphomas of mucosa-associated lymphoid tissue (MALT) type develop against a background of chronic inflammation and have functional autoantigen receptors. Because they respond to environmental factors in vivo, the expression of costimulatory molecules, which play a key role in the differentiation of normal B-lymphocytes and in T-/B-cell interaction, may be critical in early MALT-type lymphoma pathogenesis until further chromosomal aberration leads to progression. We found a high number of tumor-infiltrating T-lymphocytes (TITLs) in all low-grade MALT-type lymphomas. The TITLs in low-grade lymphomas were activated and expressed a memory and immunocompetent phenotype. Reverse transcriptase-polymerase chain reaction analyses and immunohistochemistry confirmed the presence of CD40-ligand and Fas-ligand in 80% of low-grade lymphomas. In contrast to the TITLs, the tumor B cells did not express CD40-ligand or Fas-ligand in vivo or in vitro. Moreover, the cytokine profile in vivo suggested a Th2/Th3-weighted profile (interleukin-10, interleukin-13, transforming growth factor beta(1)) rather than Th1-weighted (interferon-gamma, interleukin-2). By interphase fluorescence in situ hybridization analysis the translocation t(11;18)(q21;q21) was found in four of nine (44%) cases studied. Interestingly, there was a four times higher proliferation and survival rate of purified t(11;18)-positive tumor B cells in vitro, although there were no significant profile differences from the TITLs in vivo. The finding of essential costimulating molecules in low-grade MALT-type lymphomas in vivo indicates a locally directed cognate T-/B-cell interaction. Consequently, a potentially equipped inflammatory background may not only determine the fate of autoreactive B-cells, but is also crucial to lymphoma maintenance and progression.
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PMID:Expression of costimulatory molecules in low-grade mucosa-associated lymphoid tissue-type lymphomas in vivo. 1059 32

X-linked chronic granulomatous disease (CGD) derives from defects in the CYBB gene, which encodes the gp91-phox component of NADPH oxidase. We studied the molecular basis of the disease in a kindred with variant CGD, due to a single base substitution at the sixth position of CYBB first intron. The patients' phagocytes have been shown previously to greatly increase superoxide release in response to interferon-gamma (IFN-gamma) in vitro and in vivo. We examined CYBB gene expression in an Epstein-Barr virus (EBV)-transformed B-cell line from 1 patient in this kindred. These cells showed markedly decreased levels of CYBB transcripts in total RNA (5% of normal) and nuclear RNA (1.4% of normal), despite equal CYBB transcription rates in the CGD and control cells. Incubation with IFN-gamma produced a 3-fold increase in CYBB total messenger RNA (mRNA) levels in the patient's cells, and decreased nuclear transcripts to undetectable levels. Reverse transcriptase-polymerase chain reaction analysis of RNA splicing revealed a preponderance of unspliced CYBB transcripts in the patient's nuclear RNA. In vitro incubation with IFN-gamma increased by 40% the ratio of spliced relative to unspliced CYBB mRNA in nuclei from the CGD B-cell line. Total RNA harvested from the same patient's monocytes, on and off therapy with IFN-gamma, showed a similar improvement in splicing. We conclude that IFN-gamma partially corrects a nuclear processing defect due to the intronic mutation in the CYBB gene in this kindred, most likely by augmentation of nuclear export of normal transcripts, and improvement in the fidelity of splicing at the first intron.
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PMID:Interferon-gamma improves splicing efficiency of CYBB gene transcripts in an interferon-responsive variant of chronic granulomatous disease due to a splice site consensus region mutation. 1082 42

Functional chemokine receptors and chemokines are expressed by glial cells within the CNS, though relatively little is known about the patterns of neuronal chemokine receptor expression and function. We developed monoclonal antibodies to the CCR1, CCR2, CCR3, CCR6, CXCR2, CXCR3 and CXCR4 chemokine receptors to study their expression in human fetal neurons cultured from brain tissue as well as the clonally derived NT2.N human neuronal cell line (NTera 2/cl.D1). Specific monoclonal antibody labeling demonstrated expression of CCR2, CXCR2, CXCR3 and CXCR4 on neurons from both sources. Co-labeling studies revealed strong expression of CXCR3 and CXCR4 on both dendritic and axonal processes, with a weaker expression of CXCR2 and CCR2. Reverse transcriptase-polymerase chain reaction analysis of pure NT2.N neurons confirmed RNA expression for CCR2, CXCR2, CXCR3 and CXCR4. No changes in the neuronal labeling pattern of chemokine receptor expression were noted when NT2.N neurons were grown on a supporting layer of astrocytes, again consistent with similar patterns seen in primary human fetal brain cultures. Analysis of single-cell calcium transients revealed a robust response to stromal derived factor-1alpha (CXCR4) and melanocyte growth-stimulating activity (CXCR2), and variable response to monocyte chemoattractant protein-1 (CCR2) or interferon-gamma inducible protein-10 (CXCR3). Finally, we detected the release of monocyte chemoattractant protein-1 from pure cultures of NT2.N neurons, but not undifferentiated NT2 cells. These data indicate that individual neurons may not only co-express multiple functional chemokine receptors, but also that neurons themselves produce chemokines which may influence cellular function within the central nervous system.
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PMID:Expression of multiple functional chemokine receptors and monocyte chemoattractant protein-1 in human neurons. 1082 41

BACKGROUND-Myocardial failure is an important problem after heart transplantation. Right ventricular (RV) failure is most common, although its mechanisms remain poorly understood. Inflammatory cytokines play an important role in heart failure. We studied the expression of tumor necrosis factor (TNF)-alpha and other cytokines in donor myocardium and their relationship to the subsequent development of RV failure early after transplantation. METHODS AND RESULTS-Clinical details were obtained, and ventricular function was assessed by transesophageal echocardiography in 26 donors before heart retrieval. A donor RV biopsy was obtained immediately before transplantation, and each recipient was followed for the development of RV failure. Reverse transcriptase-polymerase chain reaction was performed to detect TNF-alpha, interleukin-2, interferon-gamma, and inducible nitric oxide synthase expression. Eight of 26 recipients (30.8%) developed RV failure. Seven of these 8 (87.5%) expressed TNF-alpha, but only 4 of the 18 (22.2%) who did not develop RV failure expressed TNF-alpha (P<0.005). As a predictor of RV failure, TNF-alpha mRNA had a sensitivity of 87.5%, a specificity of 83.3%, a positive predictive value of 70%, and a negative predictive value of 93.7%. Western blotting demonstrated more TNF-alpha protein in the myocardium of donor hearts that developed RV failure (658+/-60 versus 470+/-57 optical density units, P<0.05). Immunocytochemistry localized TNF-alpha expression to cardiac myocytes. Reverse transcriptase-polymerase chain reaction detected interferon-gamma in 2 (7.7%), interleukin-2 in 1 (3.8%), and inducible nitric oxide synthase mRNA in 1 (3.8%) of the 26 donor hearts, none of which developed RV failure. CONCLUSIONS-TNF-alpha expression in donor heart cardiac myocytes seems to predict the development of RV failure in patients early after heart transplantation.
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PMID:Tumor necrosis factor-alpha is expressed in donor heart and predicts right ventricular failure after human heart transplantation. 1089 97

In the present study, we examined the effects of the aqueous extract of Rhodiola sachalinensis root (RSE) on the expression of inducible nitric oxide (NO) synthase (iNOS) gene in RAW264.7 macrophages. RSE synergistically increased NO synthesis in interferon-gamma-primed macrophages. Reverse transcriptase polymerase chain reaction and Northern blotting analysis revealed that RSE may provide a second triggering signal for the synergistic induction of iNOS mRNA expression. Thus, iNOS-mediated NO synthesis in response to RSE may be one mechanism whereby this herbal medicine elicits its therapeutic effects.
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PMID:The aqueous extract of Rhodiola sachalinensis root enhances the expression of inducible nitric oxide synthase gene in RAW264.7 macrophages. 1137 93


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