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:2.7.7.48 (transcriptase)
9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin-dependent diabetes mellitus in nonobese diabetic (NOD) mice results from selective destruction of pancreatic islet beta-cells following islet infiltration by mononuclear leukocytes. Cytokines produced by islet-infiltrating mononuclear cells may be involved in beta-cell destruction. Therefore, we analyzed cytokine mRNA expression, by reverse-transcriptase PCR (RT-PCR) assay, in mononuclear leukocytes isolated from pancreatic islets of four groups of mice: diabetes-prone female NOD mice; female NOD mice protected from diabetes by injection of CFA at an early age; male NOD mice with a low diabetes incidence; and female BALB/c mice that do not develop diabetes. We found that mRNA levels of IL-1 beta, IL-2, IL-4, IL-10, and IFN-gamma in mononuclear cells from islets of diabetes-prone female NOD mice increased progressively as these cells infiltrated the islets from age 5 wk to diabetes onset (> 13 wk). However, only IFN-gamma mRNA levels were significantly higher in islet mononuclear cells from 12-wk-old diabetes-prone female NOD mice than from less diabetes-prone NOD mice (CFA-treated females, and males) and normal mice (BALB/c). In contrast, IL-4 mRNA levels were lower in islet mononuclear cells from diabetes-prone female NOD mice than from NOD mice with low diabetes incidence (CFA-treated females and males). Splenic cell mRNA levels of IFN-gamma and IL-4 were not different in the four groups of mice. These results suggest that islet beta-cell destruction and diabetes in female NOD mice are dependent upon intra-islet IFN-gamma production by mononuclear cells, and that CFA-treated female NOD mice and male NOD mice may be protected from diabetes development by down-regulation of IFN-gamma production in the islets.
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PMID:IFN-gamma gene expression in pancreatic islet-infiltrating mononuclear cells correlates with autoimmune diabetes in nonobese diabetic mice. 772 37

The response of IFN-gamma, IL-2 and IL-5 mRNA expression to the stimulation of concanavalin A (Con A) in peripheral blood mononuclear cells (PBMC) after bone marrow transplantation (BMT) was analyzed using reverse-transcriptase polymerase chain reaction (RT-PCR) to assess the recovery of T cell function. The subjects were 23 patients undergoing allogeneic BMT, 1 syngeneic BMT, 1 autologous BMT and 2 normal individuals. IFN-gamma mRNA expression increased after Con A stimulation in 6 patients who had limited chronic graft versus host disease (GVHD), 14 patients who did not have chronic GVHD, each one patient receiving syngeneic and autologous BMT and 2 normal individuals. On the other hand, IFN-gamma mRNA expression was not increased by Con A stimulation in 4 patients who had extensive chronic GVHD. Also, the concentration of IFN-gamma in cultured medium in a patient with extensive chronic GVHD was not detectable. A similar low response of IL-2 and IL-5 mRNA expression to Con A was observed in these patients with extensive chronic GVHD. These findings indicate that the cytokine productive capacity of T cell (IFN-gamma and IL-2 could be produced by type 1 T helper (Th1) cells and IL-5 could be produced by type 2 T helper (Th2) cells) was suppressed in patients who had extensive chronic GVHD, while that capacity was almost normal in patients without chronic GVHD and with limited chronic GVHD. Therefore, the analysis of cytokine gene response to Con A stimulation may provide useful information regarding immune reconstitution after BMT.
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PMID:Cytokine gene expression by concanavalin A-stimulated peripheral mononuclear cells after bone marrow transplantation: an indicator of immunological abnormality due to chronic graft-versus-host disease. 788 2

The cytokine effector status of CD4+ T cells from lymph nodes (LN) and the central nervous system (CNS) of SJL/J mice immunized with autoantigen in adjuvant for the induction of experimental allergic encephalomyelitis (EAE) was compared. CD4+ T cells were FACS sorted based on the levels of expression of the activation marker CD45RB. Low levels of expression of this surface marker are induced by antigen recognition and are associated with 'effector' T cell function. Reverse transcriptase polymerase chain reaction (PCR) was used to analyze the expression of different T cell cytokine genes in the sorted populations. CD45RBlow cells constituted a minority of CD4+ cells in the LN and expressed elevated levels of IL-2, IFN-gamma, and IL-4 mRNA, whereas the CD45RBlow CD4+ population did not express detectable message for these cytokines under linear PCR conditions. By contrast to the LN, CD4+ cells from the CNS were predominantly CD45RBlow and expressed readily detectable levels of IL-2 and IFN-gamma mRNA, but almost no IL-4 transcription could be detected. IL-4 mRNA levels in CNS were 100- to 250-fold lower than in LN. Also, IL-4 message could not be detected in the CNS 1 week after remission. A cytokine-specific immunocytochemical single cell staining technique was used to enumerate cytokine-producing cells in LN cell populations and in CNS infiltrates. Between 1 and 5% cells in isolated LN cells produced detectable IL-2 and IFN-gamma. By contrast, the frequency of cytokine-producing cells stained in perivascular infiltrates in frozen sections from the brains of animals with active EAE was 10-fold higher.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Selective enrichment of Th1 CD45RBlow CD4+ T cells in autoimmune infiltrates in experimental allergic encephalomyelitis. 791 Apr 82

Rapid and severe rejection remains a major obstacle to successful clinical intestinal transplantation (IT). The aggressive nature of rejection in IT has been attributed to the increased massive immune stimulus provided by large numbers of resident lymphocytes, antigen presentation capacity of enterocytes, and graft damage mediated by luminal microflora. Early small bowel expression of proinflammatory cytokines, MHC class II, and adhesion molecules may also promote IT rejection, but the lack of a mouse model has hampered extensive studies of gene expression in IT. Using a recently developed surgical model, we examined the temporal pattern of gene expression in CB6F1 (H-2b/d) vascularized, heterotopic intestinal allografts transplanted into BALB/c (H-2d) mice. Although histological evidence of rejection was not present until day 7 in allografts, Northern blot analysis demonstrated increases in TNF alpha gene transcripts as early as day 3, followed by the expression of IL-1 beta, intercellular adhesion molecule-1, and MHC class II by day 5. Using reverse-transcriptase polymerase chain reaction, IFN-gamma was detected in allografts by day 3 and persisted to day 10. In contrast, IL-2, IL-4, IL-5, and IL-6 mRNA transcripts peaked by day 5 and then decreased, suggesting that both Th1 and Th2 subsets are involved in the rejection of unmodified small bowel allografts. The early and progressive expression of TNF alpha and IL-1 beta as well as IFN-gamma, intercellular adhesion molecule-1, and MHC class II in IT rejection may contribute to the difficulty in controlling IT rejection with present immunosuppression.
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PMID:Altered gene expression of cytokine, ICAM-1, and class II molecules precedes mouse intestinal allograft rejection. 794 Jul 16

Reverse transcriptase-polymerase chain reaction showed that interleukin 3, IL-4, IL-5, IL-6, interferon-gamma and stem cell factor mRNA expression were higher in 15-deoxyspergualin-treated spleen cells than in control spleen cells. Increased IL-2 and IFN-gamma mRNA expression were observed in 15-deoxyspergualin-treated bone marrow cells. On the other hand, increased platelet counts in BALB/c-->C3H/He bone marrow chimeras were observed from days 20 to 33 in our previous work, when they were treated with 15-deoxyspergualin from days 14 to 25. In contrast, marked leukocytopenia and anemia were simultaneously observed, although a marked leukocytosis and a rapid recovery of anemia were observed on day 33 and thereafter. To analyze effects of 15-deoxyspergualin on hematopoiesis and the immune system, we examined mRNA expression in bone marrow and spleen cells from BALB/c-->C3H/He bone marrow chimeras treated with 15-deoxyspergualin from days 14 to 25. Reverse transcriptase-polymerase chain reaction showed that IL-3, IL-4, IL-6, stem cell factor, granulocyte colony-stimulating factor, and granulocyte/macrophage colony-stimulating factor mRNA expression were higher in 15-deoxyspergualin-treated chimeras than in control chimeras, indicating that these cytokines are responsible for an enhancement of hematopoiesis. It was conceivable that IL-6 supported thrombopoiesis in concert with other cytokines. On the contrary, increased IFN-gamma, IL-2, IL-3, IL-4, and IL-10 mRNA expression may play an immunosuppressive role in vivo.
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PMID:Effects of 15-deoxyspergualin in vitro and in vivo on cytokine gene expression. 797 17

Cytokine production by T cells in the cerebrospinal fluid (CSF) and central nervous system (CNS) of SJL/J mice during myelin basic protein (MBP)-induced experimental allergic encephalomyelitis (EAE) was examined. Reverse transcriptase/polymerase chain reaction (RT/PCR) was used to measure interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) mRNA levels from perfused CNS tissue (brain and spinal cord) and from cells isolated from CSF. Animals were grouped according to EAE severity, ranging from asymptomatic (adjuvant only) to severe disease (paralysis or severe paresis). Cytokine signals, normalized to actin, were almost undetectable in control tissues, and only slightly elevated in whole CNS tissue from animals with mild EAE. Both cytokine messages were strongly upregulated in CNS tissues derived from severely affected animals, consistent with previous observations correlating disease progression with infiltration by memory/effector CD4+ T cells, the major source of these cytokines. This cytokine upregulation was specific to the CNS, since other organs from the same animals did not express significant levels of IL-2 and IFN-gamma. CSF was obtained from the cisterna magna of unperfused mice and verified as such by absence of red blood cells (RBCs) and by immunoglobulin concentration orders of magnitude lower than in serum. Cytokine message was measured in RNA isolated from cells in CSF. Levels of IL-2 and IFN-gamma mRNA in CSF cells were significantly elevated in mild EAE and strongly upregulated in severe disease, correlating with those in total CNS tissue. These results confirm the CSF as representative of the immune status of the CNS and indicate a role for IL-2 and IFN-gamma in inflammatory CNS disease.
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PMID:Cytokine production by cells in cerebrospinal fluid during experimental allergic encephalomyelitis in SJL/J mice. 829 48

Inflammatory cytokines, particularly those produced by Th1 type lymphocytes, are hypothesized to play a major role in the pathogenesis of autoimmune diseases. The present studies investigated this hypothesis in the BB rat. Diabetes-prone (DP) BB rats develop spontaneous hyperglycemia and thyroiditis. Coisogenic diabetes-resistant (DR) BB rats do not develop either disorder spontaneously, but both diseases are induced by depletion of RT6+ T cells. Reverse transcriptase-PCR was used to measure mRNA encoding type 1 and type 2 cytokines. In both DP and RT6-depleted DR rats, IFN-gamma mRNA was present in islets before and during disease onset. IL-2 and IL-4 mRNAs were minimal or undetectable in infiltrated islets but present in activated peripheral T cells. IL-10 mRNA was present at low abundance in infiltrating T cells. These observations suggested a Th1 type inflammatory response, and consistent with this interpretation, we observed that mRNA encoding the p40 chain of IL-12 was also present before and during disease onset. Similar cytokine mRNA profiles were observed in the thyroids of RT6-depleted DR rats and in the islets of DP rats treated with prophylactic parenteral insulin to prevent diabetes. We conclude that IFN-gamma and IL-12 may play a major role in the expression of insulitis and thyroiditis in the BB rat, that Th1 lymphocytes may predominate over Th2 lymphocytes in these inflammatory lesions, and that prevention of diabetes by insulin is not associated with an alteration in the cytokine gene profile of islet infiltrating cells.
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PMID:Cytokine gene expression in islets and thyroids of BB rats. IFN-gamma and IL-12p40 mRNA increase with age in both diabetic and insulin-treated nondiabetic BB rats. 855 12

Distinct cytokine-producing T cell subsets are well known to play a major role in IgE production and to be differentially regulated in allergic patients, although the characterization of the type 1/type 2 cytokine pattern in PBMC during allergic responses remains to be clearly defined. The aim of this study was to determine whether different cytokine profiles are observed directly in PBMC of atopic donors. We attempted to study several cytokines (IL-2, IFN-gamma, IL-4, IL-10 and IL-13) using not only ELISA but also polymerase chain reaction (PCR) techniques, because the frequency of cytokine-producing cells in peripheral blood is very low. All the patients were selected during their acute symptomatologic phase. Data showed a significantly higher production of IL-4 (P = 0.05) and IL-10 (P < 0.005) as determined by ELISA in phytohaemagglutinin (PHA)/phorbol myristate acetate (PMA)-stimulated mononuclear cells of atopic donors compared with controls, although spontaneous IL-4 production without stimulation was never detected within either atopic or control groups. The reverse-transcriptase (RT)-PCR technique appeared to be advantageous in that it allowed the detection of the spontaneous expression of cytokine mRNA in cells without stimulation. We found a clear expression of IL-4 mRNA spontaneously in all atopic patients, whereas normal donors in most cases did not show specific signals (P < 0.0001). Less differences between atopic subjects and controls were found in IL-10 mRNA expression. Although the technique of RT-PCR amplification used in this study is semiquantitative, a reproducible and significant (P < 0.001) enhancement of IL-10 mRNA expression was observed in atopic donors. A heterogeneous expression of IL-13 mRNA was observed in individuals from the two groups studied, although mean levels in atopic donors were slightly enhanced compared with controls (P = 0.02). Furthermore, we did not observe any alteration in the expression of the type 1-derived cytokines such as IFN-gamma and IL-2. In addition, we showed a lack of correlation between the expression of serum IgE (total or specific) and spontaneous IL-4 mRNA expression. This study showed a tendency of PBMC from atopic donors to express a type 2-like cytokine pattern, with IL-4 as the most discriminatory cytokine. Additionally, as the level of serum IgE has a low predictive value in allergic disease, and as the elevated expression of IL-4 that we found was not correlated with serum IgE, we could strongly suggest that the measurement of IL-4 in blood mononuclear cells may be of great value in the analysis of allergic responses in atopic donors.
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PMID:Differential spontaneous expression of mRNA for IL-4, IL-10, IL-13, IL-2 and interferon-gamma (IFN-gamma) in peripheral blood mononuclear cells (PBMC) from atopic patients. 856 69

CTLA4Ig, a fusion protein that blocks CD28-B7 costimulation, was studied in a LEW to F344 rat model of chronic cardiac rejection. In rats treated with a single dose of CTLA4Ig (0.5 mg intraperitoneally) 2 d after transplantation, allografts survived significantly longer ( > 70 d in 64%) than in untreated controls or rats treated with control Ig (all rejected within 25 d). Only 25% of grafts from rats treated with a single, high dose of cyclosporine A (25 mg/kg, 2 d after transplantation) survived longer than 70 d. Reverse transcriptase PCR and immunostaining analyses of tissue from 75-d, CTLA4Ig-treated allografts showed reduced expression of the T cell factor IFN-gamma and macrophage activation factors monocyte chemoattractant protein-1, inducible nitric oxide synthase, and galactose/N-acetylgalactosamine macrophage lectin, as well as TGF-beta. Grafts from longterm survivors ( > 120 d) treated with CTLA4Ig showed significant reductions in the frequency and severity of arteriosclerosis in comparison with cyclosporine A-treated rats. Thus, T cell activation is a proximal event in the cascade that culminates in the arteriosclerosis of chronic rejection. Strategies for blocking T cell costimulation may help prevent chronic rejection in clinical transplantation.
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PMID:Chronic cardiac rejection in the LEW to F344 rat model. Blockade of CD28-B7 costimulation by CTLA4Ig modulates T cell and macrophage activation and attenuates arteriosclerosis. 860 41

We determined the expression of Th-2 type cytokines, interleukin-4 (IL-4) and IL-5, and of the Th-1 type cytokine, interferon-gamma (IFN-gamma), in the Brown-Norway rat. Rats were intraperitoneally sensitized with ovalbumin and 21 days later were either exposed to ovalbumin or saline aerosol. The value -log PC300 (PC300 = concentration of acetylcholine needed to increase baseline lung resistance by 300%) was 2.49 +/- 0.15 in sensitized, exposed rats, was higher than in sensitized, saline-exposed or naive rats (1.54 +/- 0.27 and 1.63 +/- 0.06 respectively, P < 0.05). There was a significant increase in eosinophils in bronchoalveolar lavage fluid and in airway submucosal airway tissues in the sensitized exposed group. Reverse-transcriptase polymerase chain reaction was performed on total lung RNA using primers for IL-4, IL-5, IFN-gamma and beta-actin. IL-4 and IL-5 mRNA levels in control and sensitized saline-exposed rats were not detectable, but increased levels were found in sensitized and ovalbumin-exposed rats with levels of 0.25 +/- 0.01 and 0.98 +/- 0.02% of beta-actin mRNA as assessed by densitometric measurements. Expression of IFN-gamma mRNA was significantly reduced in sensitized and ovalbumin-exposed rats. As in asthmatic airways, there is an increased expression of Th-2 cytokines, IL-4 and IL-5, together with a reduction in the Th-1 cytokine, IFN-gamma, thus supporting a role for Th-2 cytokines in allergic eosinophilic inflammation.
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PMID:Expression of Th-2 cytokines interleukin-4 and -5 and of Th-1 cytokine interferon-gamma in ovalbumin-exposed sensitized Brown-Norway rats. 869 Apr 57


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