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:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of cysteamine (2-aminoethanethiol, MEA) and its disulfide, cystamine, on the human immunodeficiency virus (HIV-1) expression in chronically infected promonocytic cells (U1), T cell line (ACH-2), and peripheral blood monocyte-derived macrophages (MDM) were investigated. U1 and ACH-2 cells constitutively express low levels of virus, which is increased by the addition of tumor necrosis factor (TNF-alpha), interleukin 6 (IL-6), granulocyte-macrophage-colony-stimulating factor (GM-CSF), and other inducers. Cystamine, in noncytotoxic doses, suppressed in a concentration-dependent fashion the induction of HIV-1 expression mediated by TNF-alpha, IL-6, GM-CSF, and monokine-enriched monocyte culture supernatants in both U1 and ACH-2 cells as determined by HIV-1 reverse transcriptase (RT) activity. Similarly, HIV-1 expression was substantially reduced in the cystamine-treated primary MDM cultures compared with the untreated control cultures. The addition of cystamine into HIV-1 chronically infected MDM (12 days after infection was established) also suppressed 80-90% of RT activity in comparison to the untreated controls. HIV-1 (Bal) infected MDM cultures (without cystamine treatment) demonstrated giant syncytium formation, whereas cystamine-treated cultures lacked the giant syncytia induced by HIV-1 infection. Cystamine also inhibited LPS-induced TNF production in MDM. In contrast to cystamine, cysteamine showed no significant effects on either the monokine-induced HIV-1 expression in U1 or ACH-2 or acute and chronic HIV-1 infection in MDM.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cystamine inhibits HIV type 1 replication in cells of monocyte/macrophage and T cell lineages. 763 61

Continuous ambulatory peritoneal dialysis is known to interfere with the normal inflammatory responses of macrophages in the peritoneal cavity. Commercial peritoneal dialysis solution (CDS) has been shown to inhibit tumor necrosis factor alpha (TNF alpha) release from LPS stimulated peritoneal macrophages. To further dissect the mechanism of this inhibition, we used human blood-derived macrophages or the murine macrophage cell line, P388D1, that were stimulated with LPS after pretreatment with CDS, and tested TNF alpha mRNA levels by Northern hybridization or reverse transcriptase polymerase chain reaction. Time course studies demonstrated that CDS lowered TNF alpha mRNA levels within 15 minutes of pretreatment of cells. In addition, the CDS inhibited DNA binding activity of NF-kappa B that is probably involved in regulation of LPS-mediated transcriptional activation of the TNF alpha gene. Inhibition was dependent on both the low pH and the lactate in the CDS, but was independent of the osmolarity or glucose concentration. The rate of catabolism of TNF alpha mRNA was not affected by CDS as demonstrated by actinomycin D chase experiments. Thus, impairment of LPS-stimulated macrophage function by CDS is associated with low TNF alpha mRNA which may be the result of the low activity of NF-kappa B. Since NF-kappa B is involved in transcription regulation of a large number of "early activation" genes, CDS may interfere with the production of additional immunomodulatory proteins that are encoded by genes possessing NF-kappa B site(s) in their promoter region.
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PMID:Commercial dialysate inhibits TNF alpha mRNA expression and NF-kappa B DNA-binding activity in LPS-stimulated macrophages. 764 22

Studies in murine models of osteoporosis have suggested the hypothesis that ovarian steroids may control osteoclastic bone remodeling by limiting the production of interleukin-6 (IL-6) from osteoblasts and bone marrow stromal cells. To investigate this hypothesis in a human model, we have examined 12 separate strains of normal human osteoblasts (HOB) and 11 separate strains of human bone marrow stromal cells (HBMSC) and determined whether ovarian steroids regulate the induction of IL-6 by interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha) or IL-1 + TNF. Treatment with IL-1, TNF or IL-1 + TNF resulted in the induction of IL-6 from both cell types with IL-1 + TNF inducing a synergistic induction of IL-6 in HOB (24- to 324-fold) and HBMSC (35-288 fold). Addition of 17 beta-estradiol or progesterone did not significantly alter IL-6 messenger RNA or protein levels in either HOB or HBMSC cultures stimulated with IL-1, TNF or IL-1 + TNF. Cultures incubated up to 96 h with the steroids did not affect IL-6 expression. Furthermore ovarian steroids did not affect IL-6 production in either HBMSC cultures representative of preosteoblasts or HOB cultures representative of highly differentiated osteoblasts. Specific chloramphenicol acetyl transferase assays and reverse transcriptase-polymerase chain reaction studies also demonstrated that the lack of an estrogen effect was not due to the failure of HOB to express functional estrogen receptors. Therefore, we conclude that the regulation of human osteoclastic bone remodeling by ovarian steroids does not occur through the direct regulation of IL-6 gene transcription or protein secretion in either early stages of osteoblast differentiation or the differentiated osteoblast.
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PMID:Production of interleukin-6 in human osteoblasts and human bone marrow stromal cells: evidence that induction by interleukin-1 and tumor necrosis factor-alpha is not regulated by ovarian steroids. 764 14

Airway inflammation is characterized by leukocyte extravasation around the peribronchial mucosa and into the airway of the lung. In the present study we utilized a model of airway inflammation induced by intratracheal challenge with soluble parasite (Schistosoma mansoni) egg Ag (SEA) in presensitized mice. The subsequent inflammatory response and leukocyte recruitment consists of early neutrophil (8 to 24 h) and later eosinophil (48 to 72 h) infiltration into the interstitium and airway. Little neutrophil and no eosinophil recruitment was observed in presensitized control mice challenged with vehicle. Multiple studies have demonstrated a crucial role for TNF-alpha during inflammatory responses. In these experiments we investigated the role of TNF-alpha in Ag-specific eosinophilic airway inflammation. Measurement of TNF-alpha expression by reverse transcriptase-PCR and ELISA in whole lung homogenates of SEA-challenged mice demonstrated an early increase in TNF-alpha levels (1 to 8 h). To determine the specific role of TNF-alpha in leukocyte recruitment during airway inflammation, mice were treated with soluble TNF-alpha receptor linked to an Fc Ab molecule (sTNFr-:Fc). This treatment has previously been used to effectively neutralize TNF in vivo. Intratracheal SEA-challenged mice treated with sTNFr-FC demonstrated significantly decreased leukocyte recruitment into the lung and airway. The inflammatory response in the lungs in sTNFr-Fc-treated mice was significantly decreased throughout the study period, as compared with control mice. An approximate decrease in early neutrophil infiltration into the airway was observed when sTNFr-Fc was administered 2 h before the Ag challenge. Eosinophil infiltration was also diminished when sTNFr-Fc was administered before Ag challenge. Interestingly, when sTNFr-Fc was administered therapeutically 24 h after Ag challenge, the eosinophil response was nearly abrogated at 48 h after challenge. These studies indicate that TNF-alpha acts as an initial inflammatory cytokine that subsequently regulates both early neutrophil infiltration and eosinophil recruitment into the lung and airspace.
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PMID:TNF-alpha mediates recruitment of neutrophils and eosinophils during airway inflammation. 773 Jun 42

A previous study reported the increased expression of the cytokine TNF in the adipose tissue of genetically obese rodents. To examine this paradigm in humans, we studied TNF expression in lean, obese, and reduced-obese human subjects. TNF mRNA was demonstrated in human adipocytes and adipose tissue by Northern blotting and PCR. TNF protein was quantitated by Western blotting and ELISA in both adipose tissue and the medium surrounding adipose tissue. Using quantitative reverse transcriptase PCR (RT-PCR), TNF mRNA levels were examined in the adipose tissue of 39 nondiabetic subjects, spanning a broad range of body mass index (BMI). There was a significant increase in adipose TNF mRNA levels with increasing adiposity. There was a significant correlation between TNF mRNA and percent body fat (r = 0.46, P < 0.05, n = 23). TNF mRNA tended to decrease in very obese subjects, but when subjects with a BMI > 45 kg/m2 were excluded, there was a significant correlation between TNF mRNA and BMI (r = 0.37, P < 0.05, n = 32). In addition, there was a significant decrease in adipose TNF with weight loss. In 11 obese subjects who lost between 14 and 66 kg (mean 34.7 kg, or 26.6% of initial weight), TNF mRNA levels decreased to 58% of initial levels after weight loss (P < 0.005), and TNF protein decreased to 46% of initial levels (P < 0.02). TNF is known to inhibit LPL activity. When fasting adipose LPL activity was measured in these subjects, there was a significant inverse relationship between TNF expression and LPL activity (r = -0.39, P < 0.02, n = 39). With weight loss, LPL activity increased to 411% of initial levels. However, the magnitude of the increase in LPL did not correlate with the decrease in TNF. Thus, TNF is expressed in human adipocytes. TNF is elevated in most obese subjects and is decreased by weight loss. In addition, there is an inverse relationship between TNF and LPL expression. These data suggest that endogenous TNF expression in adipose tissue may help limit obesity in some subjects, perhaps by increasing insulin resistance and decreasing LPL.
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PMID:The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity, weight loss, and relationship to lipoprotein lipase. 773 78

The pro-inflammatory molecules, tumor necrosis factor alpha (TNF alpha), interleukin 1 (IL-1), interleukin 6 (IL-6), and prostaglandin E2 (PGE2), are postulated to have a role in human pregnancy and parturition. The ability of interleukin 4 (IL-4) to suppress the production of TNF alpha, IL-1, IL-6, and PGE2 by activated monocytes prompted us to investigate a possible regulatory role for IL-4 in human gestation. Immunohistochemical techniques were used to show that human amnion epithelium stained positively for IL-4. Tissue from both the first (n = 5) and third (n = 46) trimester expressed immunoreactive IL-4, which was detected by the use of four antihuman IL-4 monoclonal antibodies. Analysis of mRNA by reverse transcriptase-polymerase chain reaction (RT-PCR) on RNA extracts of amnion epithelial cells indicated that they were the source of IL-4. One of the anti-IL-4 antibodies used stained IL-4 protein associated with the basement membrane of the amnion epithelium. The mechanism of this association was investigated. IL-4 was shown to be a heparin-binding cytokine, which would enable it to bind to components of the extracellular matrix. Thus, this study identified a previously undescribed cellular source of IL-4, implicating a role for IL-4 in human gestation. Additionally, glycosaminoglycan binding may regulate IL-4 activity in vivo.
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PMID:Interleukin 4 production by human amnion epithelial cells and regulation of its activity by glycosaminoglycan binding. 778 6

Human monocyte-derived macrophages (MDM) were infected with the viral strain HIV1/Ba-L and with the clinical isolates HIV1/DAS and HIV1/PAR. Kinetics of tumour necrosis factor alpha (TNF alpha) and interleukin-6 (IL6) production were investigated for 28 days after infection. At the early stages of infection we observed significant TNF alpha and IL6 secretion 2 to 10 h after infection, whatever the viral strain we used. During the late events of MDM infection, TNF alpha and IL6 were detected over 16 to 21 days following HIV1 infection, at the time of high viral replication. Pretreatment of MDM with a TNF alpha synthesis inhibitor, RP 55778, 4 h prior to HIV infection induced a modified cytokine pattern during the first ten hours of infection: TNF alpha production was totally inhibited despite comparable amounts of IL6. At the late phases of the cell culture, a decrease in magnitude of both viral and cytokine production as well as a delay in the appearance of reverse transcriptase activity and cytokine secretion peaks were observed in RP-55778-pretreated and HIV1-infected MDM cultures. Similar results were obtained after pretreatment of HIV1/DAS-infected MDM cultures with an anti-TNF alpha monoclonal antibody.
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PMID:Treatment of human monocyte-derived macrophages with a TNF alpha synthesis inhibitor prior to HIV1 infection: consequences on cytokine production and viral replication. 780 Sep 46

Chemotactic cytokines, or chemokines, are likely mediators of inflammatory cell recruitment in renal allograft rejection. A recent addition to the C-X-C super gene family branch of chemokines is epithelial-derived neutrophil-activating factor-78 (ENA-78). ENA-78 is a 78-amino acid peptide with neutrophil-activating and chemotactic properties. This chemokine is unique in that it was originally isolated and cloned from an IL-1-stimulated human pulmonary epithelial cell line, A549. In this article, we investigated whether ENA-78 could be produced by human renal epithelial cells. We found that primary cultures of human renal cortical epithelial cells with tubular cell attributes could express significantly increased steady state levels of ENA-78 mRNA when stimulated with IL-1 beta (2.0 ng/ml). In addition, these cells also secreted significantly increased ENA-78 antigen compared with controls when stimulated with IL-1 beta (2.0 ng/ml). Other proinflammatory agonists, including TNF alpha, IFN gamma, and LPS failed to stimulate ENA-78 steady state mRNA or antigenic peptide production by renal cortical epithelial cells. In addition, biopsy tissue from acutely rejecting human renal allografts had higher copy number of ENA-78 mRNA compared with nonrejecting renal allograft controls using a quantitative reverse transcriptase polymerase chain reaction method with a mutant ENA-78 transcript. In the proinflammatory milieu of the rejecting renal allograft, IL-1 beta produced by host and donor mononuclear cells may drive ENA-78 production by allograft tubule cells, thus effecting leukocyte recruitment into the tubulointerstitial compartment.
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PMID:Epithelial-derived neutrophil-activating factor-78 production in human renal tubule epithelial cells and in renal allograft rejection. 783 12

We recently identified a gene that is induced by lymphocyte activation (ILA). The sequence of the full-length 1.4-kb cDNA characterized ILA as a new member of the nerve growth factor/tumor necrosis factor (NGF/TNF) receptor family and the human homologue of the murine T-cell-specific receptor 4-1BB. The present study demonstrates ILA mRNA isoforms at 4.4, 4.0, and 1.8 kb in poly-A+ RNA from activated, but not from resting human peripheral blood T lymphocytes. A reverse transcriptase-polymerase chain reaction (RT-PCR) assay was used to study tissue distribution and regulation of ILA expression. The gene was induced in T lymphocytes by phytohemagglutinin (PHA), phorbol myristate acetate (PMA), and antibody to CD3, in B lymphocytes by PMA and antibodies to cell surface Ig, and in blood monocytes by interleukin-1 beta (IL-1 beta), lipopolysaccharide (LPS), and PMA. In T lymphocytes, ILA mRNA was detectable 1.5 hours after stimulation, reached maximal levels at 8 hours, and declined to background levels by 48 hours. Induction of ILA mRNA required protein synthesis and was primarily due to increased transcription. Actinomycin D reduced ILA mRNA levels in activated lymphocytes 50% within 30 minutes, demonstrating a relatively short half-life of this mRNA. Analysis of nonlymphoid cells showed that ILA mRNA was not detectable in resting cells. However, in contrast to the lymphoid-specific expression of the murine 4-1BB gene, ILA was detected in nonlymphoid cells, including epithelial and hepatoma cells after stimulation with IL-1 beta. ILA was not detectable in several brain derived cell lines. The ILA cDNA encodes a 30-kD protein as demonstrated by in vitro translation, and this protein is immunoprecipitated by antisera that were raised against ILA peptides or a glutathione-S-transferase fusion protein. Flow cytometry showed expression of ILA protein on a subset of activated T or B lymphocytes. In conclusion, activation-dependent expression of ILA is found not only in T lymphocytes, but also in B lymphocytes, monocytes, and diverse nonlymphoid cell types.
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PMID:ILA, the human 4-1BB homologue, is inducible in lymphoid and other cell lineages. 784 93

Antigen presentation by endogenous glial cells is postulated to regulate reactivity of immune cells that gain entry into the CNS. We have previously observed, using a mixed lymphocyte reaction (MLR) system, that adult human-derived microglia can function as antigen-presenting cells (APC) for immediately ex vivo CD4+ T cells in a primary MLR (1 degree MLR) whereas astrocytes could not. We have now found that fetal human astrocytes can support CD4+ T cell proliferation in the presence of exogenous human recombinant (r) IL-2, and that astrocytes can support the continued proliferation of CD4+ T cells previously sensitized to sister astrocyte cultures in a secondary MLR. Additionally, adult human microglia, seeded into the nonpriming astrocyte: CD4+ T cell cocultures at non-T cell-stimulatory concentrations of 1000-5000 microglial cells per well, could reverse the inability of astrocytes to present antigen in the primary MLR. To examine the cellular basis for the inability of human astrocytes to function as APCs in the primary MLR, astrocyte- and microglial-enriched populations were established from human embryonic and adult brain, respectively, and analyzed for their ability to synthesize cytokines potentially relevant as accessory signals in the MLR. Microglia had transcript as determined by the reverse transcriptase-polymerase chain reaction (RT-PCR) and protein as determined by bioassay for IL-1 alpha, IL-6, and TNF alpha. Human fetal astrocytes had transcript for IL-6 but not for IL-1 alpha or TNF alpha under basal culture conditions and following IFN gamma stimulation. The addition of human rIL-1 from 1-50 U/ml could reverse the inability of astrocytes to present antigen in the primary MLR. These studies demonstrate that although in vitro highly enriched cultures of astrocytes absent of microglia cannot present antigen to immediately ex vivo blood-derived CD4+ T cells in the MLR, in situ, with the cooperative help of microglia-derived cytokines or accessory surface molecules, astrocytes may function as central nervous system APCs.
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PMID:Antigen presentation by human fetal astrocytes with the cooperative effect of microglia or the microglial-derived cytokine IL-1. 789 Nov 40


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