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)

15-deoxyspergualin (DSG)-treated BALB/c spleen cells showed increased spontaneous proliferation and increased alloreactive mixed lymphocyte reactions (MLRs) when a 3-h treatment was carried out. However, when spleen cells were treated with DSG for 5 days without washing out DSG, decreased spontaneous proliferation was observed, although alloreactive MLRs against C3H/He and C57BL/6 alloantigens were increased. In contrast, cyclosporin A (CsA) induced markedly decreased alloreactive MLRs. Decreased concanavalin A (Con A)- and pokeweed mitogen (PWM)-induced responses were observed in spleen cells treated with DSG for 3 h; whereas increased phytohemagglutinin (PHA)-induced responses were observed. On the other hand, increased Con A- and PHA-induced responses were observed in spleen cells treated with DSG for 2 days, whereas PWM-induced responses were decreased. CsA-treatment induced markedly decreased mitogen-induced responses. These results suggest that the immunosuppressive mechanism of DSG differs from that of CsA. Reverse transcriptase-polymerase chain reaction (RT-PCR) method showed that interleukin 1 beta (IL-1 beta), IL-2, IL-3, IL-4, IL-5, and leukemia inhibitory factor (LIF) mRNA expression in DSG-treated spleen cells were increased by Con A stimulation, thus indicating that DSG modulates cytokine gene expression and inducing immunosuppressive mechanisms different from CsA.
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PMID:Effects of 15-deoxyspergualin on proliferative responses and cytokine gene expression in vitro. 775 Sep 88

The purpose of this study was to determine whether or not membrane-bound and soluble forms of IL-4 receptors are expressed by isolated subsets of murine lung fibroblasts and to evaluate the potential functional consequences of IL-4 receptor triggering. Recent studies demonstrate that IL-4-synthesizing Th2 cells and mast cells are present in increased numbers in the lung during inflammation and fibrosis, suggesting that IL-4 may play a regulatory role in these events. We hypothesize that pulmonary fibroblasts and subsets thereof are intimately involved in this inflammatory response and that IL-4 is an active player in stimulating fibroblast collagen synthesis and hyperproliferation, creating a fibrotic environment in the lung. The fibroblast subsets used in these experiments differ not only in surface expression of the thymocyte-1 (Thy-1) Ag, but also in function and morphology. We now report the novel finding that IL-4 receptors are present at discordant levels on Thy-1+ and Thy-1- lung fibroblasts. IL-4R level and affinity were analyzed using a monoclonal anti-IL-4R Ab and equilibrium binding analysis with 125I-labeled IL-4. Reverse transcriptase PCR demonstrated the presence of mRNA for membrane-bound and soluble IL-4R. Lung fibroblast subsets secrete soluble IL-4R protein at dramatically different levels, as detected by an ELISA. Thy-1+ and Thy-1- lung fibroblasts were treated with IL-4 to determine whether this cytokine was profibrotic. Thy-1+ fibroblasts responded to IL-4 by proliferating and up-regulating collagen production. In contrast, Thy-1- fibroblasts proliferate to a lesser degree than Thy-1+ fibroblasts and were not stimulated to secrete increased levels of collagen. Overall, these results suggest that elevated levels of IL-4 at a site of injury could result in the development of fibrosis by enhancing fibroblast subset proliferation and collagen synthesis.
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PMID:Subsets of murine lung fibroblasts express membrane-bound and soluble IL-4 receptors. Role of IL-4 in enhancing fibroblast proliferation and collagen synthesis. 790 5

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

Interleukin-6 (IL-6) induced increased, leukocyte and platelet counts on around day 20 when it was administered into [BALB/c-->C3H/He] bone marrow chimeras from day 1 to day 12. Increased leukocyte counts and hemoglobin (Hb) levels were also observed at around day 60 and from day 41 to 80, respectively. On the other hand, hematopoietic recovery in [C3H/He-->C3H/He] bone marrow chimeras injected with IL-6 was different from that in [BALB/c-->C3H/He] bone marrow chimeras, showing no delayed and long-lasting increase in Hb levels but showing an early and transient increase in Hb levels and platelet counts. Sera from [BALB/c-->C3H/He] bone marrow chimeras injected with IL-6 showed predominant productions of IL-3 and/or IL-4. Reverse transcriptase polymerase chain reaction (RT-PCR) showed that stem cell factor (SCF) mRNA expression was increased in bone marrow or spleen cells from [BALB/c-->C3H/He] bone marrow chimeras injected with IL-6 on day 36. Furthermore, we analyzed influence of IL-6 on graft-versus-host disease (GVHD) in [BALB/c-->C3H/He] bone marrow chimeras injected with IL-6. Decreased survival days and body weights were not observed when compared with the control. Histopathological changes of the liver due to GVHD were also not obvious. However, alloreactive mixed lymphocyte reactions (MLRs) were readily detected although cytotoxic T cells were not generated. Since H-2 typing showed that donor-type chimerism was predominantly observed, it was suggested that split tolerance might be induced by IL-6 administration. Increased IL-2 levels were not detected in sera from [BALB/c-->C3H/He] bone marrow chimeras injected with IL-6 whereas IL-4 was detected in the same sera, indicating that type 2 helper T (TH2) cells appeared to be predominantly generated. These results suggest that IL-3/IL-4 and SCF appeared to synergistically support delayed effects on hematopoiesis in [BALB/c-->C3H/He] bone marrow chimeras injected with IL-6 although early effects appeared to be mediated mainly by IL-6 directly or indirectly. Furthermore, IL-6 could induce split tolerance in [BALB/c-->C3H/He] bone marrow chimeras via a preferable activation of TH2 type cells without inducing severe GVHD.
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PMID:In vivo administration of interleukin-6 in murine allogeneic bone marrow chimeras: early and delayed enhancement of hematopoiesis accompanied with split tolerance but not with graft-versus-host disease. 798 20

Lymphohematopoiesis occurs in the densely packed environment of the intramedullary spaces. Primitive lymphohematopoietic stem cells exist in close apposition to a variety of supportive cells including both hemopoietic and nonhemopoietic lineages. Using an in vitro long-term Dexter liquid culture system, we have established that a variety of cytokines are produced constitutively by such stromal cells in culture. These cytokines include Steel factor, interleukin-6 (IL-6), and colony-stimulating factor (CSF-1). Granulocyte-CSF and granulocyte-macrophage-CSF mRNA can be detected after refeeding of cultures, although in quiescent cultures message for these factors is difficult to detect. Interleukin-3, IL-4, and IL-5 are not detectable by standard Northern blot analysis or bioassay of condition media. However, IL-3--detectable by reverse-transcriptase PCR and biologic activity--was confirmed by growth of factor-dependent cells on stromal cells with IL-3 antibody blocking of such growth. Stem cells resident on such stromal cells are mirrored by the high proliferative potential colony-forming cell assay and are responsive to a relatively large number of cytokines, with Steel factor being of central importance, appearing to be a critical component of various synergistic combinations. Steel factor allows reduced levels of other factors in such combinations and works early in a temporal sequence. Hematopoietic stem cells can engraft in normal nonmyeloablated hosts. Using a male/female BALB/c transplantation model, we have shown high rates of engraftment into normal animals, out after marrow infusion to 25 months, after marrow infusion and that post-5-fluorouracil bone marrow is quite deficient in such engraftment.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:In vitro and in vivo studies of stromal niches. 799 65

Macrophages are regulated by hormones, cytokines, and other substances. We examined the effects of glucocorticoids (GC) on serum amyloid A (SAA) mRNA expression using an antisense SAA3 probe, and found that dexamethasone (DEX) and triamcinolone (TC) increased SAA3 mRNA expression by macrophage cell lines in a time- and concentration-dependent manner. Both an RNA polymerase II antagonist, alpha-amanitin, and a specific GC antagonist, RU38486, inhibited the enhancement of SAA3 mRNA expression by DEX. These results show that GC lead to enhanced SAA3 mRNA transcription. Nuclear run-on experiments supported these results. Enhanced expression of SAA3 mRNA by DEX was accompanied by production of SAA3 protein. Interferon-gamma (IFN-gamma) alone showed any effect on SAA3 mRNA expression. Enhanced SAA3 expression by DEX was inhibited by treatment with IFN-gamma in a dose-dependent manner. Either transforming growth factor (TGF)-beta 1 or interleukin (IL)-4 alone showed no effect on SAA3 mRNA expression, but suppressed DEX-induced SAA3 expression. The timing of the effects of IFN-gamma and TGF-beta 1 on DEX-induced SAA3 expression differed: IFN-gamma showed its effect between 30 h before and 18 h after DEX administration, whereas TGF-beta 1 showed an effect when administered concomitantly with DEX and in the late stages after DEX administration. IL-4 mildly suppressed DEX-induced SAA3 expression when given 12 h before and after DEX administration.
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PMID:Enhancement of murine serum amyloid A3 mRNA expression by glucocorticoids and its regulation by cytokines. 799 55

Although parathyroid hormone-related peptide (PTHRP) is produced by adult T cell leukemia (ATL) cells and causes hypercalcemia in ATL patients, very little is known about the regulation of PTHRP gene expression in the leukemic cells. The present study was undertaken to clarify the role of T cell growth factor, interleukin-2 (IL-2), in the expression of PTHRP gene, using a human T cell leukemia virus type I (HTLV-I)-infected T cell line, MT-2. Recombinant human IL-2 caused a transient increase in the steady state level of PTHRP messenger RNA (mRNA) in MT-2 cells, and a maximal effect was observed at 3-6 h. The effect of IL-2 was dose dependent, with a maximal response being observed at 10(-10) M. A monoclonal antibody against IL-2 receptor (anti-Tac antibody) inhibited the IL-2-induced increase in PTHRP mRNA level. Recombinant human IL-1, IL-3, IL-4, and IL-6 failed to increase PTHRP mRNA level. Nuclear run-off transcription assay showed that the transcription rate of the PTHRP gene was modestly increased by IL-2. In addition, IL-2 caused a substantial increase in the stability of PTHRP mRNA, compared with control cells in which the apparent half-life of PTHRP mRNA was less than 30 min after RNA synthesis was inhibited by the RNA polymerase II inhibitor, dichlorobenzimidazole riboside. The secretion of PTHRP, as determined by both a newly established immunoradiometric assay using recombinant human PTHRP(1-87) as the standard and an RIA using an antibody against PTHRP(109-141), was increased by IL-2 but not by IL-1, IL-3, IL-4, or IL-6. The IL-2-induced increase in PTHRP secretion was completely inhibited by the addition of anti-Tac antibody. These results demonstrate that IL-2 stimulates the production and secretion of PTHRP by HTLV-I-infected T cells through specific binding to IL-2 receptor and that the effect of IL-2 is mediated by a posttranscriptional as well as a transcriptional mechanism. It is suggested that IL-2 may be involved in an auctocrine/paracrine fashion not only in the proliferation of HTLV-I-infected T cells but also in the enhanced production and secretion of PTHRP and thus the development of hypercalcemia in ATL patients.
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PMID:Interleukin-2 increases production and secretion of parathyroid hormone-related peptide by human T cell leukemia virus type I-infected T cells: possible role in hypercalcemia associated with adult T cell leukemia. 809 24

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


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