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:3.1.27.1 (RNase)
16,360 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transforming growth factor (TGF)-beta and interleukin (IL)-10 inhibited lipopolysaccharide (LPS)-induced macrophage production of the inflammatory cytokines tumor necrosis factor-alpha (TNF), IL-1 alpha, and IL-1 beta by contrasting post-transcriptional mechanisms. TGF-beta acted slowly and late, as it required 12-16 h to exert a suppressive effect, and inhibited TNF production even when added 6 h after LPS. TGF-beta affected neither the level of TNF mRNA, the release of preformed TNF nor the degradation of TNF. Thus, TGF-beta appeared to inhibit translation of TNF mRNA. IL-10 not only suppressed TNF release to a 25-fold greater extent than TGF-beta, but also inhibited release of IL-1. In contrast to TGF-beta, IL-10 acted on an early step in cytokine production, its effect being maximal 3 h after addition of LPS. Unlike TGF-beta, IL-10 markedly suppressed TNF, IL-1 alpha, and IL-1 beta mRNA levels. However, this was accomplished without suppressing transcription of the corresponding genes. Moreover, cycloheximide antagonized the IL-10-dependent reduction in cytokine mRNA levels. Thus, IL-10 may induce a ribonuclease active on cytokine transcripts or may induce a protein that enhances the susceptibility of TNF, IL-1 alpha, and IL-1 beta mRNAs to ribonucleolytic action. We conclude that IL-10 and TGF-beta induce different phenotypes of macrophage deactivation, and deactivate macrophages by different mechanisms: IL-10 promotes degradation of cytokine mRNA, while TGF-beta primarily suppresses translation.
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PMID:Contrasting mechanisms for suppression of macrophage cytokine release by transforming growth factor-beta and interleukin-10. 142 77

Murine IL-10, initially identified as a product of Th2 CD4+ T cell clones, is known to be produced by a variety of hematopoietic cells. The cellular and tissue expression of IL-10 in vivo is not known and could be relevant to understanding its functions. We examined in vivo, expression of IL-10 mRNA using RT-PCR in various normal and mutant mice and after irradiation. In addition, expression was studied during rejection of an i.p. injection of P815 tumor cells. Total RNA was extracted from whole organs; standard RT-PCR, semiquantitative PCR, and RNase protection assays were performed. In normal mice IL-10 mRNA was detectable in all tissues surveyed. Semiquantitative PCR allowed an estimation of the relative levels of IL-10 mRNA in tissues. IL-10 mRNA in spleen and kidney of nude mice and SCID mice was detectable in normal amounts. Expression of IL-10 mRNA was increased in spleen and kidney in a dose-dependent fashion after irradiation. During allogeneic stimulation IL-10 mRNA was increased in spleen and kidney as demonstrated by the PCR and RNase protection assays. In conclusion, IL-10 mRNA is detectable by PCR in many organs of normal mice and is largely T and B cell-independent. The increase of IL-10 mRNA in spleen and kidney during an intraperitoneal T cell response, at a time when IFN-gamma mRNA is known to be increased in the same organs, suggests a complex systemic interaction between IL-10 and other cytokines during rejection. Moreover, the ubiquitous tissue distribution and the increased levels of steady state IL-10 mRNA after irradiation suggest that this molecule plays a general role in the biology of all tissues and may explain some of the immunosuppressive effects of ionizing radiation.
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PMID:Tissue distribution of IL-10 mRNA in normal mice. Evidence that a component of IL-10 expression is T and B cell-independent and increased by irradiation. 811 46

Rat cytokine synthesis inhibitory factor (IL-10) was cloned. Like mouse and human IL-10 (mIL-10, hIL-10), rat IL-10 exhibits strong DNA and amino acid sequence homology to the open reading frame in the Epstein-Barr virus, BCRFI. The supernatant of COS-7 transfectants with rat IL-10 was found to inhibit the production of IFN-gamma by murine Th1 cells. A probe from the rat IL-10 was used in an RNase protection assay to demonstrate that IL-10 was expressed in LPS-stimulated rat spleen and FACS-purified OX-42-reactive peritoneal macrophages. The production of IL-10 by macrophages, as shown in the current study, suggests that IL-10 may have an autocrine function in inflammation.
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PMID:Molecular cloning of rat cytokine synthesis inhibitory factor (IL-10) cDNA and expression in spleen and macrophages. 848 57

Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease in which cytokines are thought to play an important role in beta-cell destruction and immune regulation. A major target of beta-cell autoimmunity in IDDM is the enzyme glutamate decarboxylase (GAD). We hypothesized that cytokines in the insulitis lesion modulate the synthesis of GAD. This may, in turn, modify the rate of beta-cell destruction. Accordingly we cultured rat islets in the presence and absence of cytokines, and measured synthesis of both isoforms of GAD, GAD65 and GAD67, by [35S]methionine incorporation and immunoprecipitation with a rabbit antiserum that recognizes both GAD65 and GAD67. Incubation of islets with interleukin (IL)-1 beta (1 ng/ml, 24 h), tumour necrosis factor alpha (TNF-alpha; 200 units/ml, 24 h) or interferon gamma (IFN-gamma; 500 units/ml, 72 h) significantly decreased the synthesis of both GAD65 and GAD67, but reduced neither total protein synthesis nor insulin accumulation in the medium or content. Incubation of islets for 24 h in IFN-alpha (1000 units/ml), TNF-beta (50 ng/ml), IL 2 (1000 units/ml), IL-4 (100 ng/ml), IL-6 (10 ng/ml), IL-10 (20 ng/ml), IL-12 (10 ng/ml) or transforming growth factor beta 2 (TGF-beta 2; 5 ng/ml) did not significantly alter GAD65 or GAD67 synthesis. Inhibition of GAD65 and GAD67 protein synthesis by IL-1 beta, TNF-alpha or IFN-gamma was reversed by co-incubation with the nitric oxide synthase inhibitor, NG-monomethyl arginine (NMMA). Expression of both GAD65 and GAD67 mRNA, measured by RNase protection assay, was also decreased by IL-1 beta and completely restored to baseline levels by NMMA. Thus the synthesis of both isoforms of islet GAD is selectively decreased in the presence of IL-1 beta, TNF-alpha or IFN-gamma by a NO-mediated mechanism, probably at the level of cytokine gene transcription. As GAD autoimmunity has been previously shown to have a pathogenic role in an animal model of IDDM, its inhibition by cytokines might limit the immune response, thereby regulating the rate of beta-cell destruction in IDDM.
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PMID:Cytokine regulation of glutamate decarboxylase biosynthesis in isolated rat islets of Langerhans. 876 Mar 54

Pharmacological control of interleukin-12 (IL-12) production may be a key therapeutic strategy for modulating immunological diseases dominated by type-1 cytokine responses. In this study, we investigated the effects of pentoxifylline on the production of IL-12 by human blood mononuclear cells and primary human monocytes stimulated with heat-killed Staphylococcus aureus Cowan strain I (SAC) or lipopolysaccharide (LPS). Pentoxifylline potently suppressed production of IL-12 in a concentration-dependent manner. In these same experiments, tumour necrosis factor-alpha (TNF-alpha) production was inhibited and IL-10 and prostaglandin E2 (PGE2) production was enhanced by treatment with pentoxifylline. Suppression of IL-12 production by pentoxifylline was found to be independent of several known endogenous inhibitors of IL-12, such as IL-10, transforming growth factor-beta (TGF-beta), IL-4 and PGE2. RNase protection assays revealed that pentoxifylline inhibited accumulation of both IL-12 p40 and p35 mRNA, suggesting a predominant mRNA locus for pentoxifylline-induced IL-12 inhibition. Low levels of pentoxifylline added to the suppression of IL-12 production by suboptimal inhibiting doses of dexamethasone, suggesting that this drug combination may have therapeutic utility. These results provide a firm rationale for the use of pentoxifylline in clinical trials of immunological disorders characterized by inappropriate type-1 immune responses.
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PMID:Inhibition of human interleukin-12 production by pentoxifylline. 922 17

Changes that occur in the local draining lymph nodes including, changes in cell surface markers and cytokine gene expression were studied over the first 4 weeks of a primary, Ostertagia ostertagi infection of the abomasum. Cells recovered from the abomasal lymph nodes (ABLN) after infection showed a decrease in the percentage of CD3+ cells, and an increase in the percentage of IgM+ cells and cells bearing the TcR1 marker. These changes were coincident with an increase in the proportion of activated cells (II-2R). Analysis of mitogen-stimulated ABLN cells by RNase protection assay (RPA) showed a dramatic reduction in IL-2 and IFN-gamma transcription after infection. In addition, analysis of unstimulated ABLN cells by competitive RT-PCR showed a similar decrease in demonstrable levels of IL-2 mRNA, but IL-10, IL-4 and IFN-gamma mRNA levels were elevated.
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PMID:Cytokine profile induced by a primary infection with Ostertagia ostertagi in cattle. 934 40

Neonatal animals of several species are more tolerant of hyperoxic exposure than are adults. However, the mechanisms of increased neonatal tolerance are unknown, as are the cell types that contribute to oxygen resistance. This study examined hyperoxic lung injury in neonatal and adult C57BL/6 mice. Adults and neonatal mice were exposed to > 95% oxygen for 78 h and 10 days, respectively. Lung mRNAs were assayed by RNase protection assay. After 72 h of exposure, the messages encoding tumor necrosis factor alpha (TNF-alpha) and interleukin 1 beta and 6 (IL-1 beta, IL-6) were increased 2-fold in adult lungs. However, at this time point these mice are near or at lethality. No alterations in neonatal lung mRNAs were detected until 7 days of oxygen exposure. At that time neonatal mice demonstrated increases in lung mRNAs encoding TNF-alpha, IL-1 beta, and IL-6 of 3-, 5-, and 8-fold, respectively. Acute alveolitis and slight edema were detected, but lethality wasn't observed until 10 days of exposure. In situ hybridization in neonatal mice suggests accumulation of TNF-alpha and IL-1 beta transcripts in pulmonary interstitial macrophages and in a subset of neutrophils after 7 days of exposure. Messages encoding IL-1 alpha, IL-2, IL-3, IL-4, IL-5,IL-10 interferon-gamma (IFN-gamma), and TNF-beta were not altered from controls in either adult or neonatal mice at any time point examined. In conclusion, adult mice demonstrate little change in cytokine mRNA until lethality is imminent, whereas newborn mice demonstrate an acute induction of TNF-alpha, IL-1 beta, and IL-6 early in the development of hyperoxic injury, which suggests that a rapid cytokine response early in the development of hyperoxic injury may play an important role in the adaptation of neonatal lungs to toxicity from prolonged oxygen exposure.
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PMID:Comparison of adult and newborn pulmonary cytokine mRNA expression after hyperoxia. 935 35

Epstein-Barr virus (EBV) transformed human B cells proliferate indefinitely in vitro, and it has been proposed that cytokine-mediated autocrine loops contribute to the maintenance of the lymphoblastoid phenotype. We used a novel multiprobe RNase protection assay to quantify cytokine mRNA species expressed by EBV-transformed lymphoblastoid cell lines (LCL), derived either by the transformation of B cells with B95-8 or wild-type EBV or by the in vitro outgrowth of EBV-associated B cell lymphomas to identify cytokines that are commonly expressed in all LCL and thus more likely to be essential for immortalization of B cells. All 16 LCL expressed high levels of tumor necrosis factor (TNF)alpha, TNFbeta, and transforming growth factor (TGF)beta1 mRNA, while interleukin (IL)-10 transcripts were detected in most LCL but at a lower level. Expression of IL-1alpha, IL-1beta, IL-6, IL-12p35, IL-12p40, IL-13 and IFNgamma mRNA was variable among the LCL tested. Granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-2, IL-4, and IL-5 mRNA were undetectable in all LCL. Furthermore, we found that IL-10, TNFalpha, and TNFbeta mRNA were induced in EBV-negative B cell lines after infection with EBV. These data define common versus idiosyncratic patterns of cytokine expression by LCL and, in the former case, such cytokines as TNFalpha, TNFbeta, and IL-10 emerge as strong candidates that are essential for the autocrine regulation of EBV-immortalized B cells.
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PMID:Common and idiosyncratic patterns of cytokine gene expression by Epstein-Barr virus transformed human B cell lines. 947 49

Interplay between T-helper-1 (Th1) and T-helper-2 (Th2) cells is considered important in the development of acute allograft rejection and many other immune-mediated disease processes. Existing methods for evaluating expression of Th1 and Th2 cytokines, including reverse transcriptase polymerase chain reaction (RT-PCR), RNase protection assay (RPA), immunohistochemistry, and enzyme-linked immunosorbent assay (ELISA) all have limitations; alternate techniques to quantify cell populations expressing specific cytokine proteins, generate statistically analyzable data, and allow simultaneous identification of cytokine-secreting cell type are needed. To this end, we adapted a flow cytometric technique for intracellular cytokine immunofluorescence staining for use with cells isolated from solid tissue. To demonstrate the utility of the method, we determined the number of CD4+ and CD8+ cells secreting the prototypical Th1 and Th2 cytokines, interferon (IFN)-gamma, and interleukin (IL)-4 in acutely rejecting murine cardiac allografts. We also measured the cytokine production via ELISA, RPA, and semiquantitative competitive RT-PCR. The number of CD4+ cells producing IFN-gamma increased as rejection proceeded, in agreement with previous data; we detected no IL-4 production at any time, although relatively low numbers of IL-10-producing cells were identified. In addition, a high percentage of CD8+ cells, which outnumber CD4+ cells at day 6 after transplant, also produce IFN-gamma, suggesting that cytotoxic lymphocytes contribute significantly to the local cytokine milieu. This new application of intracellular cytokine staining provides a powerful methodology for studying transplantation immunology. The method may also be easily adapted to the study of other immune-mediated processes.
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PMID:Interferon-gamma-secreting T-cell populations in rejecting murine cardiac allografts: assessment by flow cytometry. 981 29

Microglia are the resident macrophages of the brain, and when activated, have functions including cytokine production, phagocytosis and antigen presentation. The class II MHC genes encode proteins that present antigenic peptides to helper T cells, leading to T cell activation and the development of an antigen-specific immune response. Class II MHC gene expression is strictly regulated by the class II transactivator (CIITA) transcription factor. In this study, we investigated the effects of various immunomodulatory cytokines on IFN-gamma induction of class II MHC and CIITA gene expression in microglia, both primary microglia and a murine microglial cell line, EOC 20. By flow cytometry analysis we show that IFN-gamma-induced surface expression of class II MHC molecules on EOC 20 cells can be inhibited by the cytokines TGF-beta1, IL-4 and IL-10, but not IL-13. Using a ribonuclease protection assay, we have found that TGF-beta1, IL-4 and IL-10 act by inhibiting the expression of IFN-gamma-induced CIITA mRNA and, in turn, class II MHC mRNA. TGF-beta1, IL-4, and IL-10 inhibition of IFN-gamma-induced CIITA mRNA accumulation was not due to destabilization of CIITA mRNA, suggesting an effect at the level of transcription. In primary murine microglia, IL-10 and TGF-beta1 inhibited IFN-gamma-induced CIITA and class II MHC expression. However, a discordant effect of IL-4 was noted in that IL-4 enhanced IFN-gamma-induced CIITA and class II MHC expression in primary microglia. Although some differences are observed between EOC 20 cells and primary microglia in terms of responsiveness to TGF-beta, IL-4 and IL-10, CIITA and class II MHC gene expression are coordinately modulated.
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PMID:Class II transactivator and class II MHC gene expression in microglia: modulation by the cytokines TGF-beta, IL-4, IL-13 and IL-10. 1022 95


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