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 anticancer agent hydroxyurea (HU) was previously found to cause dose-dependent adrenal activation in the rat. The increased secretion of corticosterone (CORT) that results appeared to protect animals against HU toxicity, which was dramatically enhanced in adrenalectomized (ADX) rats. Similarities with the endocrine and toxicological profiles of proinflammatory cytokines such as interleukin (IL)-1 and tumor necrosis factor (TNF) led us to suggest that these effects of HU might be mediated by an increased synthesis of these cytokines. The goal of this study was therefore to demonstrate that HU induces the gene expression and synthesis of proinflammatory cytokines in vivo. Intact and ADX rats were treated with HU, mRNA was extracted from spleen cells 2 and 24 hr after treatment and message levels for IL-1 alpha, IL-2, IL-4, IL-6, TNF alpha and interferon-gamma were evaluated using the reverse transcriptase-polymerase chain reaction technique. In some experiments, circulating levels of CORT and TNF were also measured. We found that transcripts of the proinflammatory cytokines, TNF, IL-6 and (though less clearly) IL-1 alpha, were expressed in the majority of intact rats treated with HU but were absent or less evident in most controls. In contrast, gene expression of IL-2, IL-4 and interferon-gamma was not influenced by drug treatment. Adrenalectomy markedly enhanced the effects of HU. Twenty-four hours after administration of the drug, the expression of TNF and IL-6 mRNAs was still higher in ADX rats compared with intact animals. Parallel measurements of plasma CORT levels revealed that gene expression of IL-1 alpha and, to a lesser extent, TNF was inversely related to levels of circulating CORT. Adrenalectomy per se caused a significant increase in plasma TNF levels compared with intact controls. Hydroxyurea elicited significant increases in circulating TNF in both ADX and intact rats. These findings lend support to our working hypothesis and provide an explanation for both the rise in glucocorticoid secretion induced by HU in intact rats and the increase in lethality observed in animals with disruptions of the hypothalamo-pituitary-adrenal axis.
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PMID:Hydroxyurea induces the gene expression and synthesis of proinflammatory cytokines in vivo. 899 31

Recent evidence indicates that membrane-bound costimulatory molecules of the B7 family are important for T-cell activation and are upregulated in IFN gamma-stimulated human microglia and in multiple sclerosis active lesions. In this study we have performed a detailed analysis of B7-1 and B7-2 expression and regulation in cultured mouse glial cells using immunocytochemical and semi-quantitative reverse transcriptase-polymerase chain reaction techniques. In an immortalized mouse microglial cell line (BV-2), expression of B7-1 and B7-2 was enhanced by interferon-gamma (IFN gamma). IFN gamma was a weak inducer of B7-2 mRNA and immunoreactivity in microglia primary cultures obtained from the neonatal mouse brain, whereas lipopolysaccharide, tumour necrosis factor-alpha, colony-stimulating factors and interleukin-1 beta did not affect microglial B7-2 expression. Combined IFN gamma and lipopolysaccharide treatment very effectively upregulated the B7-2 gene expression and immunoreactivity in microglia, but not in astrocytes. In both glial cell types, expression of B7-1 was not induced by any of the above agents. Among known microglia/macrophage deactivators, interleukin-10, prostaglandin E2 and cAMP-elevating agents, but not transforming growth factor-beta 1 and interleukin-4, inhibited B7-2 transcripts and immunoreactivity in IFN gamma/LPS-stimulated microglia, thus suggesting possible paracrine and autocrine mechanisms for regulating the expression of this important T-cell costimulatory signal in the brain.
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PMID:Analysis of B7-1 and B7-2 costimulatory ligands in cultured mouse microglia: upregulation by interferon-gamma and lipopolysaccharide and downregulation by interleukin-10, prostaglandin E2 and cyclic AMP-elevating agents. 900 48

The persistence of human papillomavirus at cutaneous sites may be due to impaired trafficking of immune effector cells to the epidermis. We investigated whether HPV infection modulates cytokine mRNA expression in skin, thereby influencing local immunity. The mRNA expression of tumour necrosis factor-alpha, interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-1 receptor antagonist (IL-1ra), IL-4, IL-8, IL-10, IL-12, granulocyte macrophage colony-stimulating factor, transforming growth factor-beta, interferon-gamma and amphiregulin were assayed in cutaneous warts and normal skin by semiquantitative reverse transcriptase-polymerase chain reaction. The expression of the cytokines was heterogeneous in the specimens but, of the 12 mRNA species investigated, only IL-10 mRNA was significantly downregulated in warts compared with normal skin (P = 0.002). IL-1 alpha mRNA expression was significantly upregulated in common warts (P = 0.019) and plantar warts (P = 0.003) compared with normal skin. The expression of IL-1 alpha and IL-1ra mRNAs were significantly correlated in plantar warts (P < 0.05). Warts expressing IL-1 alpha also expressed amphiregulin, and there was a significant correlation between the expression of these two genes (P < 0.05). It is possible that IL-1 alpha expression in cutaneous warts may modulate the growth of papillomavirus-infected keratinocytes, mediated by amphiregulin, thus ensuring viral persistence.
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PMID:Cytokine mRNA expression in cutaneous warts: induction of interleukin-1 alpha. 901 32

Recently, interferon-gamma-inducing-factor (IGIF) has been described as a novel monokine that is a more potent interferon-gamma (IFN-gamma) inducer than IL-12. By cloning IGIF from affected tissue and studying IGIF gene expression, we describe for the first time a close association of this cytokine with an autoimmune disease. The non-obese diabetic (NOD) mouse spontaneously develops autoimmune insulitis and diabetes which can be accelerated and synchronized by a single injection of cyclophosphamide. IGIF mRNA was demonstrated by reverse transcriptase PCR in NOD mouse pancreas during early stages of insulitis. Levels of IGIF mRNA increased rapidly after cyclophosphamide treatment and preceded a rise in IFN-gamma mRNA, and subsequently diabetes. Interestingly, these kinetics mimick that of IL-12p40 mRNA, resulting in a close correlation of individual mRNA levels. Cloning of the IGIF cDNA from pancreas RNA followed by sequencing revealed identity with the IGIF sequence cloned from Kupffer cells and in vivo preactivated macrophages. When extending our study to macrophages of the spleen we observed that NOD mouse macrophages responded to cyclophosphamide with IGIF gene expression while macrophages from Balb/c mice treated in parallel did not. The IGIF gene position is located within the Idd2 interval on mouse chromosome 9 and therefore it is a candidate for the Idd2 susceptible gene. We conclude that IGIF expression is abnormally regulated in autoimmune NOD mice and closely associated with diabetes development.
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PMID:Active stage of autoimmune diabetes is associated with the expression of a novel cytokine, IGIF, which is located near Idd2. 902 80

IgA nephropathy (IgAN) is defined by the predominant deposition of IgA immune complexes (IC) in the glomerular mesangium. Interaction between IgA immune complexes and mesangial cells (MC) could be a linchpin for the genesis of IgAN. We studied the modulation of MC expression of IgA receptors (Fc alphaR) by selected cytokines. Binding of 125I-IgA to quiescent human MC showed 2.55 x 10(5) sites/cell with an affinity (Ka) of 3.2 x 10(7) M(-1). Addition of selected recombinant cytokines had no significant influence on Ka, but increased the number of sites/cell relative to unstimulated cells. Northern hybridization using the pHuFc alphaR cDNA probe showed time-dependent increases in mRNA expression in stimulated versus control cells. IL-6 and tumour necrosis factor-alpha (TNF-alpha) had a biphasic effect on the Fc alphaR mRNA level; at 48 h, IL-6 increased steady state mRNA levels about six-fold relative to control, TNF-alpha increased mRNA four-fold, and interferon-gamma (IFN-gamma) induced Fc alphaR mRNA two-fold. By reverse transcriptase-polymerase chain reaction (RT-PCR), the Fc alphaR expressed on human MC appears highly homologous to that expressed by U937 cells. Altered Fc alphaR expression in response to cytokines may influence the pathogenesis of IgAN by affecting deposition and/or clearance of IgA-IC in the mesangium.
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PMID:Proinflammatory cytokines regulate Fc alphaR expression by human mesangial cells in vitro. 903 Aug 82

The host-tumor interaction may play an important role in determining tumor progress. Recent studies have shown that this interaction can be influenced by the release of soluble factors by tumor cells and tumor-infiltrating lymphocytes (TIL). The aim of our study is to characterize the nature of cytokines and growth factors and their relationship to the cellular infiltrates in 16 patients with ovarian cancer using reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry. Total RNA from 20 malignant and 10 benign specimens were used to assay for expression of 12 cytokines. Additionally, monoclonal antibodies (MAbs) were used to detect T cells, CD4+ helper and CD8+ cytotoxic/suppressor T-cell subtypes, B cells, and macrophages. Our results showed the expression of transforming growth factor-beta1 (TGF-beta1), interleukin-10 (IL-10), and granulocyte-macrophage colony-stimulating factor (GM-CSF) in 19, 17, and 10 malignant specimens, P < .001, .001, and .05, respectively. Other cytokines such as interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), TNF-beta/LT, IL-2, and IL-6 were expressed in a few cases, and IL-1alpha and IL-4 expression were not detected. The benign samples did not express IL-10, but GM-CSF, TGF-beta1, and IL-8 were expressed in one, one, and four specimens, respectively. Interestingly, in four cases in which samples from the primary and relapse tumors were available for analysis, the tumors in relapse showed a significant increase for TGF-beta1 (P < .05) and a decreased trend in IL-10 mRNA levels. The source of these factors was tumor cells as detected immunohistochemically. This combined alteration of TGF-beta1 and IL-10 was associated with a significant reduction in number of TIL in general, and CD8+ and macrophages in particular (P = .036 and .049, respectively). Our findings suggest the important role of certain soluble factors in the complex process of tumor progression. Furthermore, understanding the tumor-host relationship and the factors influencing the interaction may be helpful in developing effective and innovative treatment methods.
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PMID:Tumor-host interaction: analysis of cytokines, growth factors, and tumor-infiltrating lymphocytes in ovarian carcinomas. 904 97

Human osteosarcoma cells secrete a novel C-X-C chemokine called granulocyte chemotactic protein-2 (GCP-2), which was previously identified by amino acid sequencing of the purified natural protein. In order to understand the role of this new protein in inflammatory reactions, we cloned GCP-2 DNA sequences to generate recombinant protein and specific DNA probes and primers. By means of PCR on cloned cDNA of osteosarcoma cells induced by interleukin-1 beta and fibroblasts induced by lipopolysaccharide plus dsRNA, the complete coding domain of GCP-2 was isolated. This sequence was cloned into the bacterial expression vector pHEN1 and, after induction, GCP-2 was secreted into the periplasm of Escherichia coli. Recombinant GCP-2 (rGCP-2) was purified and characterized by SDS/PAGE as a monomeric 6.5-kDa protein and by amino-terminal sequencing. The chemoattractive potency of GCP-2 for neutrophilic granulocytes was about 10-times less than that of interleukin-8 and the minimal effective dose was 10 ng/ml. However, at optimal dose (100 ng/ml) the maximal chemotactic response was comparable with that of interleukin-8. Both characteristics correspond with those of natural GCP-2. In addition, intracellular calcium release in neutrophils by recombinant GCP-2 was achieved with as little as 10 ng/ml. Quantitation studies using reverse transcriptase and the polymerase chain reaction revealed higher GCP-2 mRNA production in normal fibroblasts than in tumor cells. When compared with epithelial-cell-derived neutrophil-activating peptide-78 (ENA-78) mRNA, the GCP-2 mRNA levels were higher in all cell lines tested. In addition, GCP-2 and ENA-78 expression seem to be differentially regulated in that phorbol ester and lipopolysaccharide have opposing effects on their mRNA induction in diploid fibroblasts and epithelial cells, respectively. Interleukin-1 was demonstrated to be a general inducer for both chemokines, while interferon-gamma down-regulates their mRNA expression. The availability of recombinant GCP-2 together with the quantitation studies on mRNA expression will help to further elucidate the biological role of GCP-2 during the inflammatory response.
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PMID:Cloning, bacterial expression and biological characterization of recombinant human granulocyte chemotactic protein-2 and differential expression of granulocyte chemotactic protein-2 and epithelial cell-derived neutrophil activating peptide-78 mRNAs. 905 43

In the normal brain, low levels of cytokines are observed, whereas inflammatory disorders of the central nervous system are characterized by an up-regulation of cytokine production. The cellular sources for cytokines in the central nervous system are largely undefined. In the present study, we have analyzed intracerebral cytokine production in normal and Toxoplasma gondii-infected mice using immunohistochemistry, in situ hybridization, flow cytometry of brain-derived leukocytes, and reverse transcriptase polymerase chain reaction detection in various subpopulations of inflammatory cells. In the normal brain, neurons and choroid plexus epithelia expressed interleukin (IL)-1 beta and IL-10. Microglia/macrophages produced IL-1 beta, IL-10, and tumor necrosis factor-alpha In Toxoplasma encephalitis, these cell types exhibited increased levels of the respective cytokines. In addition, microglia/macrophages showed a de novo expression of inducible nitric oxide synthase. CD4+ and CD8+ T cells, which were recruited to the brain, produced IL-2, IL-10, tumor necrosis factor-alpha, and interferon-gamma. IL-4 was exclusively detectable in CD4+ T cells, whereas CD8+ T cells showed expression of IL-1 beta. As chronic Toxoplasma encephalitis was not associated with neuronal degeneration and an up-regulation of neurotrophic factors, some cytokines may also exert neurotrophic and/or neuroprotective properties.
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PMID:Expression pattern and cellular origin of cytokines in the normal and Toxoplasma gondii-infected murine brain. 906 Aug 39

Previous results indicate that induction of inducible nitric-oxide synthase (iNOS) expression may be kept suppressed by the endogenous NO level as produced by a constitutive NOS (cNOS) enzyme. In cell types possessing both cNOS and iNOS, this may represent an evident paradox. Here, we report that lipopolysaccharide and interferon-gamma, which are able to strongly induce iNOS in astrocytoma cells, can rapidly inhibit the NO production generated by the constitutive NOS isoform, thus obtaining the best conditions for iNOS induction and resolving the apparent paradox. In fact, a 30-min treatment of T67 cells with the combination of lipopolysaccharide plus interferon-gamma (MIX) strongly inhibits the cNOS activity, as determined by measuring [3H]citrulline production. In addition, the effect of MIX is also observed by measuring nitrite, the stable breakdown product of NO: a 30-min pretreatment of T67 cells with MIX is able to reduce significantly the N-methyl-D-aspartate-induced nitrite production. Finally, using reverse transcriptase-polymerase chain reaction, we have observed that a 30-min treatment of T67 cells with MIX does not affect expression of mRNA coding for the neuronal NOS-I isoform. These results suggest the novel concept of a possible role of a cNOS isoform in astrocytes as a control function on iNOS induction.
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PMID:Bacterial lipopolysaccharide plus interferon-gamma elicit a very fast inhibition of a Ca2+-dependent nitric-oxide synthase activity in human astrocytoma cells. 906 11

Recently, much attention has been given to the possible role of lymphocytes and their soluble products in causing and maintaining allergic inflammation. The aim of this study was to assess the production of mRNAs for interleukins (IL) in bronchoalveolar lavage (BAL) cells obtained from allergic asthmatics after challenge with the relevant allergen in the period between early and late reactions. We evaluated BAL fluid cells obtained from six asthmatic subjects and four nonatopic controls. Challenge was performed with the relevant allergen. BAL fluid cells were obtained by fiberoptic bronchoscopy and bronchoalveolar lavage. To detect mRNA encoding each cytokine in BAL cells we used a reverse transcriptase polymerase chain reaction method. We evaluated IL-1 alpha, -2, -4, -5, -6, -13, and granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon-gamma (IFN-gamma). mRNAs for IL-1 alpha, -2, -4, -5, and IFN-gamma were detected in all of the atopic subjects; mRNAs for IL-6 and GM-CSF were found in five asthmatics; and mRNA for IL-13 was found in one patient only. In contrast, no mRNAs for IL-2, -4, -5, -6, -13, and GM-CSF were detected in the nonatopic healthy controls; mRNA for IL-1 alpha was found in one out of four normal subjects; and mRNA for IFN-gamma was evidenced in two of four subjects. The cellular environment in BAL fluids from allergic asthmatics before the clinical appearance of the late airway reaction shows an unrestricted expression of mRNA for cytokines. The local cytokine milieu could have an important role in the modulation of bronchial inflammation and in the appearance of allergic symptoms.
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PMID:Expression of cytokine mRNA in bronchoalveolar lavage cells from atopic asthmatics before late antigen-induced reaction. 908 47


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