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)

Th1 cytokines are thought to play a key role in islet inflammation and destruction in insulin-dependent diabetes mellitus (IDDM). We studied this hypothesis in the diabetes-prone (DP)-BB and the diabetes-resistant (DR)-BB rats that are used as a model of human IDDM. The DP-BB rat develops spontaneous autoimmune diabetes at the age of 11-14 weeks. In the DR-BB rat, diabetes is inducible by depletion of RT6+ lymphocytes and coadministration of polyinosinic:polycytidylic acid (Poly I:C). We used reverse transcriptase-polymerase chain reaction (RT-PCR) and semi-quantitative PCR techniques to examine mRNA expression of Th1 and Th2 cytokines in inflamed islets and thyroids from DP-BB and DR-BB rats. We observed that in DP-BB and in treated DR-BB rats, the levels of TCR beta, IFN-gamma and IL-12p40 mRNA increase with disease progression. In contrast, expression of message for IL-2 and IL-4 is minimal to undetectable in DP-BB and RT6-depleted DR-BB animals at any age. Message for IL-10 is detectable in DP and DR islets; however, its level of expression does not change with disease progression. A similar cytokine mRNA profile is observed in inflamed thyroids from acutely diabetic RT6-depleted DR-BB rats. Incubation of 10 wk old DP islets for 48 h in the presence of anti-CD3 antibody, followed by an incubation with rIL-2 for an additional 5-7 days, results in an expansion of T lymphocytes, and these cells express high levels of IFN-gamma and IL-10 mRNA. Our results suggest that autoimmunity in DP-BB and DR-BB rats is mediated by Th1 lymphocytes and that IFN-gamma and IL-12 are likely to play a key role in islet and thyroid inflammation and destruction in IDDM.
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PMID:Evidence that Th1 lymphocytes predominate in islet inflammation and thyroiditis in the BioBreeding (BB) rat. 881 66

Previous in vivo and in vitro studies have presented various abnormalities of cellular immunity in patients with IgA nephropathy (IgAN). In the present study, we described increased expression of HLA-DR antigens on peripheral natural killer cells (NK cells) in relation to altered cytokine interactions. The numbers of HLA-DR expressing NK cells were enumerated by two-color flow cytometry and found to be significantly increased in patients with IgAN. Peripheral blood mononuclear cells were then fractionated into pure NK cells by a magnetic cell-sorting system and analyzed concerning expression of messages of interleukin (IL)-2, IL-4, tumor necrosis factor (TNF)-alpha, and interferon (IFN)-gamma by semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR). Among the four cytokines, only the IFN-gamma message was significantly increased in patients' NK cells. Furthermore, intensity of the IFN-gamma message in NK cells showed positive correlation with the percentage of HLA-DR-positive NK cells from the same patient. Then we assayed serum levels of IL-2, IL-12, and IFN-gamma by enzyme-linked immunosorbent assay (ELISA) and the levels of IL-12 and IFN-gamma showed positive correlations with HLA-DR expression on NK cells. Creatinine clearance of the patients was reevaluated 36 months later, and patients with high HLA-DR on NK cells tended to show faster deterioration of renal function than patients with lower HLA-Dr expression. On the basis of these findings, we suggested that HLA-DR-positive NK cells in patients with IgAN form an "activated" population that produces IFN-gamma, and this unique cell population may be maintained by multiple factors and be involved in the development and progression of IgAN.
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PMID:Increase of HLA-DR-positive natural killer cells in peripheral blood from patients with IgA nephropathy. 883 77

In NOD mice, autoimmune recognition and destruction of pancreatic islet beta-cells appear to be independently regulated: all mice develop cellular infiltration of the islets (insulitis), but not all develop diabetes. The destructive potential of the insulitis lesion may depend on the balance between the two CD4+ T-cell subsets. TH1 and TH2, that mediate cellular-cytotoxic and humoral responses, respectively. With a semi-quantitative reverse transcriptase-PCR assay, we examined whether the disease process was reflected in the profiles of TH1 (IL-2, IFN-gamma and IL-12) and TH2 (IL-4, IL-6 and IL-10) cytokine mRNAs expressed in pancreata of NOD mice. Pancreata rather than isolated islets were examined to minimize manipulation ex vivo to preserve the expression of cytokine transcripts in vivo. At age 6 weeks, when 70% of mice had insulitis, all cytokine transcripts were detected in most pancreata, and their expression levels corresponded to the degree of insulitis. Similarly, during induction of diabetes with cyclophosphamide all transcripts were detected and levels corresponded with the degree of insulitis. In one-year-old mice without diabetes, all transcripts were detected but levels did not correspond to the degree of insulitis. Thus, in pancreata of NOD mice with different degrees of insulitis, we were unable to demonstrate, at the RNA level, polarisation of cytokine expression into either a TH1 or TH2 profile. This finding does not, however, exclude expression of distinct cytokine transcripts by immuno-inflammatory cells within the islet lesion, which might be revealed by in situ hybridization.
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PMID:Both TH1 and TH2 cytokine mRNAs are expressed in the NOD mouse pancreas in vivo. 887 65

Intracerebral infection of susceptible mouse strains with Theiler's murine encephalomyelitis virus (TMEV) results in an immune-mediated demyelinating disease (TMEV-IDD) similar to human multiple sclerosis (MS). Although the etiology of MS remains unknown, a role of an infectious agent has been implicated in its onset. Previously we have shown the ability of bacterial lipopolysaccharide (LPS) to alter susceptibility to TMEV-IDD in genetically resistant C57BL/6 mice. In this study, the potential of LPS to alter pathogenicity of a low/non-pathogenic variant of TMEV was investigated. After intraperitoneal treatment of genetically susceptible SJL/J mice with LPS before and during viral infection, 80-100% of the mice developed clinical symptoms, while without LPS treatment none of the mice were affected. However, clinical severity in these LPS-treated mice was much milder than the level induced by the wild type pathogenic virus. Increased susceptibility to the disease after LPS treatment did not correlate with splenic T cell proliferative responses against viral antigens. However, by reverse transcriptase polymerase chain reaction (RT-PCR) analyses, an early increase in the production of Th1-type proinflammatory cytokine messages (e.g., interferon-gamma [IFN-gamma] and enhancement of viral persistence was observed in the CNS of LPS-treated, virus-infected animals as compared to mice infected with the variant virus alone. These results indicate that environmental factors such as a bacterial infection (e.g., LPS) promoting proinflammatory cytokine production can significantly enhance the pathogenicity of demyelination induced by a normally non-pathogenic virus.
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PMID:Treatment with lipopolysaccharide enhances the pathogenicity of a low-pathogenic variant of Theiler's murine encephalomyelitis virus. 889 89

Central nervous system (CNS) expression of two chemokine mRNAs, encoding monocyte chemoattractant protein-1 (MCP-1) and IFN-gamma-inducible protein (IP-10), was previously shown to be closely related to the onset of clinical signs of murine experimental autoimmune encephalomyelitis (EAE). Chemokine mRNAs accumulated in a striking, transient burst within astrocytes, near inflammatory leukocyte infiltrates. It remained unclear if chemokines functioned to initiate leukocyte entry into CNS tissues, or to amplify the intrathecal inflammatory reaction. To address this issue, we determined the expression of chemokine mRNAs at the earliest evidence of CNS immune-mediated inflammation. For these experiments, mice were sacrificed in pairs at varying times after immunization. Only one member of each pair was symptomatic for EAE at the time of sacrifice. Symptom presence correlated well with histological inflammation at the time of sacrifice. RNA was prepared from two CNS sites, brain and spinal cord, and expression of chemokine mRNAs was analyzed by a sensitive and quantitative reverse transcriptase/polymerase chain reaction dot-blot hybridization assay. CNS expressions of MCP-1 and IP-10 gene were correlated tightly with histological inflammation; indeed, chemokine expression was never detected in the absence of leukocyte infiltrates. In situ hybridizations showed that astrocytes expressed chemokine transcripts. These findings provide new information about mechanisms controlling chemokine mRNA expression during immune-mediated inflammation in EAE and are consistent with a role for chemokines as amplifiers of CNS inflammatory reactions.
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PMID:Central nervous system chemokine mRNA accumulation follows initial leukocyte entry at the onset of acute murine experimental autoimmune encephalomyelitis. 890 49

The molecular mechanism responsible for the age-dependent decline of natural killer (NK) cell response was examined. The responses of NK cells to poly(I:C), Con A, and LPS were compared between the young and the aged animals. We observed that both basal and induced NK cell activity declined with age. To further determine the basis for this change, an effort was made to identify the cytokine genes that might be involved. In addition, the capacity of acetyl-L-carnitine (ALC) to restore NK cell activity was evaluated. In this study, 51Cr release assay and reverse transcriptase-polymerase chain reaction assay were used to measure the NK cell activity and the changes in cytokine gene expression, respectively. Our results show that the decline in NK cell response to poly(I:C) and LPS in aged animals was correlated with decreased expression of the IFN-gamma gene. The decline in the NK cell response to Con A in aged animals was, however, independent of the expression of IL-2 or IFN-gamma genes. Although ALC was reported to restore functions of T cells and macrophages in aged animals, we found that long-term treatment (4 months) with ALC had no effect on either the basal or the induced age-dependent loss of NK cell activity. Our observations suggest that cytokine gene therapy could be a potential approach to improving or even preventing the decline of certain immune functions in the elderly.
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PMID:Involvement of cytokine gene expression in the age-dependent decline of NK cell response. 891 80

/We have studied the effect of interferon alpha (IFN-alpha) on MHC class II expression by human buccal epithelial cells (BEC), and mRNA expression by BEC and mucosal-associated mononuclear cells (MAMC). In 6 experiments, freshly collected BEC were suspended at a concentration of 1.0 x 10(5)/ml in RPMI 1640 and incubated in the presence of 0-10,000 IU/ml of human lymphoblastoid IFN-alpha (HuIFN-alpha). Zero and six hour samples were analyzed by single color flow cytometry using FITC-labeled murine IgG1 monoclonal antibody to HLA-DR. Preparations were also analyzed for expression of cytokine transcripts (IL-2, IL-4, IL-5, IL-6, IL-8, IFN-gamma, GM-CSF) by reverse transcriptase polymerase chain reaction (RT-PCR). Increasing concentrations of IFN-alpha resulted in proportionate increases in the percentage of HLA-DR + BEC (r = 0.7897, p = 0.0627) and in the percentage of HLA-DR+ staining at higher intensities (10(1) to 10(2) log fluorescence intensity) (LFI) (r = 0.4010, p = 0.0424). The percentage of HLA-DR + BEC rose from a mean of 1.5% with no IFN-alpha to 7% with 10,000 IU/ml IFN-alpha (p < 0.05). The percentage of HLA-DR + BEC staining at 10(1) to 10(2) LFI rose from a mean of 8.3% with no added IFN-alpha to 19.2% with 10,000 IU/ml IFN-alpha (p < 0.05). Unstimulated BEC constitutively expressed IL-8 and GM-CSF. IFN-alpha stimulated preparations also expressed IFN-gamma, possibly due to the presence of MAMC, which comprised 2-9% of the total cell population. These data indicated that HuIFN-alpha upregulates MHC class II expression by human BEC, possibly by enhancing IFN-gamma production by MAMC present in the culture preparations.
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PMID:Effect of interferon alpha on HLA-DR expression by human buccal epithelial cells. 891 10

This study analysed the effects of immunoregulatory cytokines on uroepithelial cell cytokine responses. The A-498 human kidney cell line was treated with the interleukins IL-2, IL-4, IL-5, IL-10, IL-12, IL-13, interferon gamma (IFN-alpha) and transforming growth factor beta (TGF-beta 1). Secreted IL-6 and IL-8 were quantitated by enzyme-linked immunoabsorbent assay (ELISA) and bioassay; IL-6 and IL-8 mRNA species were quantitated by reverse transcriptase polymerase chain reaction (RT-PCR). IL-4, IL-13, IFN-gamma, and TGF-beta 1, but not IL-2, IL-5, IL-10 or IL-12, stimulated IL-6 secretion. At high concentrations, IL-4 and IL-13 stimulated low levels of IL-8 secretion. Immunoregulatory cytokines were analysed for their ability to modify the A-498 cells' IL-6 and IL-8 secretion in response to Escherichia coli. IL-5, IL-12, IL-13 and TGF-beta 1 additively enhanced the bacterially induced IL-6 secretion, but they did not affect IL-8 secretion. The strongest affects on uroepithelial cell IL-6 and IL-8 responses in the presence of bacteria were observed in conjunction with IL-4 and IFN-alpha. IL-4 induced IL-6 production in synergy with E. coli. IFN-alpha both enhanced and inhibited IL-6 and IL-8 responses in combination with E. coli, depending on the order of stimulant addition. The results demonstrate that immunoregulatory cytokines can modify the uroepithelial cell responses to bacteria in vitro. In this way, T cells may regulate the cytokine responses of uroepithelial and possibly other mucosal epithelial cells in vivo.
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PMID:Immunoregulatory cytokines modify Escherichia coli induced uroepithelial cell IL-6 and IL-8 responses. 893 79

Primary cutaneous CD30 (Ki-1)+ large cell lymphoma (KiL) and lymphomatoid papulosis (LyP) type A are collectively termed as primary cutaneous CD30-positive lymphoproliferative disorders. We examined the cytokine profile of skin-infiltrating cells and the therapeutic efficacy of recombinant interferon-gamma (rIFN-gamma) in primary cutaneous KiL and LyP type A. By reverse transcriptase-polymerase chain reaction, mRNAs for interleukin-4 (IL-4) and IL-10 were detected in the dermis of skin lesions in all cases (three cases of KiL and four cases of LyP). In addition, tissue from one KiL patient transcribed IL-2 and IFN-gamma messages, and one LyP patient showed IL-2 mRNA. In contrast, normal skin from ten healthy donors contained mRNA for IL-2 or IFN-gamma, or both, but not for IL-4. Before the therapeutic trial of rIFN-gamma, the response of skin lesions was assessed by a predictive skin test with local injection of rIFN-gamma (0.5 x 10(6) Japan Reference Units [JRU; 1 JRU roughly corresponds to 4 NIH units]) for 3 consecutive days in two KiL and two LyP patients. Numbers of skin-infiltrating CD30+ cells were decreased, and transcription of mRNA for IL-4 and IL-10 was downregulated after the skin test in one KiL and two LyP cases. One KiL patient showed no histologic response or change in mRNA expression. In the therapeutic trial, rIFN-gamma (total doses of 1.2-4.0 x 10(7) JRU) was administered intravenously (n = 2) or locally (n = 2). In three patients who responded to the skin test, the lesions were objectively improved and the numbers of skin-infiltrating CD30+ cells were markedly decreased after the therapeutic trial. No improvement was observed in one KiL patient who did not respond to the skin test. These findings suggest that the skin-infiltrating CD30+ cells in KiL and LyP have a Th2 cytokine profile and raise the possibility that the administration of rIFN-gamma improves the conditions by inhibiting cytokine mRNA transcription and proliferation of CD30+ cells.
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PMID:Th2 cytokine mRNA expression in primary cutaneous CD30-positive lymphoproliferative disorders: successful treatment with recombinant interferon-gamma. 894 69

We previously reported that recovery of Lewis rats from experimental autoimmune encephalomyelitis (EAE) is associated with the appearance of suppressor T cells (Ts). These Ts secrete TGF-beta which down-regulates the production of inflammatory cytokines by the effector T cells that mediate this disease. In the present study, we immunized Lewis rats with myelin basic protein (MBP)+CFA, and evaluated purified T cells and MBP-activated spleen cells (SpC) during the paralytic phase (day 12) and after recovery (days 30-33) for TGF-beta and interferon (IFN)-gamma mRNA. We used reverse transcriptase-polymerase chain reaction (RT-PCR), quantitated on the basis of beta-actin mRNA. Abundant IFN-gamma mRNA was present in MBP-activated SpC obtained on day 12. In contrast, only trace IFN-gamma mRNA was detected in day 30 activated SpC, and no IFN-gamma mRNA was present in purified, nonactivated T cells obtained at either time. The level of IFN-gamma mRNA correlated with secretion of IFN-gamma as determined by ELISA on SpC culture supernatants, and with severity of adoptively transferred EAE by the activated SpC. Thus, it appears that IFN-gamma mRNA is both transcribed and translated in response to antigen activation, resulting in secretion of IFN-gamma by the disease-inducing Te. In contrast, when we used RT-PCR to investigate the expression of TGF-beta mRNA, we found the transcript present in isolated T cells and MBP-activated SpC obtained from rats at both days 12 and 30. The presence of TGF-beta mRNA at time points corresponding to both clinical EAE and recovery suggests post-transcriptional regulation of the production of this immunoregulatory cytokine.
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PMID:Regulation of cytokine gene expression in experimental autoimmune encephalomyelitis. 895 Jul 3


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