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)

Gut-derived endotoxins (lipopolysaccharide, LPS) complexed to LPS-binding protein (LBP) activate liver Kupffer cells via their CD14 receptor. Pro-inflammatory cytokines are released and this is postulated to promote liver injury. We previously demonstrated enhanced expression of CD14 endotoxin receptor after 2 weeks of alcohol administration. A similar result, based on 6 weeks of ethanol treatment, was recently reported and suggested to correlate with alcohol-induced liver injury. To establish whether this occurs prior to or after the initiation of damage, we investigated the temporal effect of continuous ethanol exposure on the expression of CD14 and the associated LBP. In addition, we studied the effect of treatment with gadolinium chloride (GdCl3) that inactivates Kupffer cells and alleviates alcohol-induced liver damage. The amount of CD14 and LBP mRNA, as determined by reverse transcriptase-polymerase chain reaction (RT-PCR), was unchanged 4-8 h after intragastric ethanol administration. However, after 24-48 h of repeated ethanol administration, CD14 and LBP mRNA both increased significantly and reached a level similar to that observed after 6 weeks of ethanol exposure by liquid diet. Immunostaining experiments with ED2 antibody demonstrated that GdCl3 efficiently inactivated Kupffer cells. However, there was no concomitant reduction in the expression of CD14 mRNA, suggesting that compensatory infiltration by ED2-negative, but CD14-positive, macrophages had occurred. Our results demonstrate that soon after the initiation of ethanol exposure, i.e. within 24-48 h, the hepatic expression of both the CD14 receptor and LBP is increased. This suggests that these increases could contribute to the initiation of alcoholic damage rather than being a consequence of the injury.
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PMID:Short-term ethanol exposure increases the expression of Kupffer cell CD14 receptor and lipopolysaccharide binding protein in rat liver. 1041 5

To identify the cellular immune processes underlying intra-ocular inflammation, aqueous humour was obtained at cataract surgery from 22 patients with clinically inactive uveitis and 24 patients with age-related cataract. mRNA expression for the cytokines IL-1beta, IL-2, IL-4, IL-6, IL-10, IL-12, interferon-gamma (IFN-gamma), transforming growth factor-beta (TGF-beta); T cell subsets CD3, CD4, CD8; monocytes and macrophages (CD14); and B cells (CD19) was measured using reverse transcriptase-polymerase chain reaction (RT-PCR) and radiometric analysis. The majority of uveitis patients demonstrated a T cell-mediated inflammatory response, predominately involving a Th1-like cytokine profile with expression of IL-2 and IFN-gamma in 16/22 and 18/22 samples, respectively. These cytokines were present in only a small number of patients with age-related cataract. This Th1-like polarization was supported by an increased expression of CD8 in a number of patients. IL-1beta was expressed in only six uveitic eyes. Only four patients expressed either IL-4 or IL-10 and no patient expressed both. TGF-beta mRNA could be detected in 18/22 uveitis patients and 15/24 controls. IL-12, the paradigmatic Th1-inducing cytokine, was absent in all samples but CD14 was expressed in the majority of patients and controls. CD19 could not be detected in any sample. The cellular infiltrate in the uveitic eyes showed clear evidence of low IL-1 and absent IL-12 expression despite a Th1-like profile and high expression of macrophages. This strongly suggests that the systemic immunosuppressive therapy used prior to surgery in some patients and/or the chronicity of the uveitis had actively suppressed/switched off macrophage function, leading to resolution of T cell activity.
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PMID:Molecular analysis of resolving immune responses in uveitis. 1046 47

The subset of human blood monocytes expressing low levels of CD14 and high levels of CD16 (CD14+CD16+) exhibits features resembling mature tissue macrophages and can be expanded in inflammatory conditions. We analyzed expression of CC chemokine receptors (CCR) in CD14+CD16+ versus CD14++ monocytes, which may be crucial for specific trafficking. Multicolor flow cytometric analysis of whole peripheral blood revealed that, as opposed to CD14++ monocytes, the CD14+CD16+ subset lacked surface expression of monocyte chemotactic protein-1 (MCP-1) receptor CCR2, however, it showed significantly higher surface expression of the macrophage inflammatory protein 1alpha (MIP-1alpha)/RANTES receptor CCR5. This was paralleled by differences in mRNA expression in the subsets, as shown by reverse transcriptase-polymerase chain reaction using sorted cells. In comparison to CD14++ monocytes, CD14+CD16+ cells expressed lower CCR2 but higher CCR5 transcript levels, whereas CCR1 levels were equivalent. Flow cytometric analysis of isolated human monocytes recovered after transendothelial chemotaxis assays revealed that the percentage of CD14+CD16+ cells was dramatically reduced in the fraction migrating toward MCP-1 compared with the fraction that did not migrate or the input, showing that polarized CCR2 expression was accompanied by a differential chemotactic responsiveness. Moreover, CD11b surface expression was preferentially up-regulated by MCP-1 in CD14++ cells but by MIP-1alpha in CD14+CD16+ monocytes, confirming the functional relevance of distinct CCR expression. The characteristics of CD14+CD16+ cells may reflect preactivation by cytokines and determine their predilective localization during specific inflammatory conditions or susceptibility to infection.
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PMID:Differential chemokine receptor expression and function in human monocyte subpopulations. 1081 Oct 11

Diabetic glomerulosclerosis is defined by increased glomerular extracellular matrix (ECM) that is mainly synthesized by mesangial cells that underwent an activation mediated by cytokines and growth factors from various cellular origins. In this study, we tested whether macrophages could infiltrate the glomeruli and influence ECM synthesis in experimental diabetes. To test our hypothesis, we initially studied the dynamics of glomerular macrophage recruitment in streptozotocin-induced diabetic rats at days 1, 2, 4, 8, 15, and 30 by using quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) on isolated glomeruli and immunohistochemistry and morphometry. We then assessed the role of macrophages on the basis of the pharmacological modulation of their recruitment by insulin or ACE inhibitor treatments and by X-irradiation-induced macrophage depletion at days 8 and 30. Macrophages were recruited within the glomeruli at the very early phase of hyperglycemia by using RT-PCR CD14 detection from day 2 and by using ED1 immunohistochemistry from day 8. This glomerular macrophage infiltration was associated with an increase in alpha1-chain type IV collagen mRNA. In parallel, the diabetic glomeruli became hypertrophic with an increase in the mesangial area. Macrophage recruitment was preceded by or associated with an increased glomerular expression of vascular cell adhesion molecule 1, intracellular adhesion molecule 1, and monocyte chemoattractant protein 1, which contributes to monocyte diapedesis. Glomerular interleukin-1beta mRNA synthesis was also enhanced as early as day 1 and could be involved in the increase in ECM and adhesion molecule gene expressions. Insulin treatment and irradiation-induced macrophage depletion completely prevented the glomerular macrophage recruitment and decreased alpha1-chain type IV collagen mRNA and mesangial area in diabetic rats, whereas ACE inhibitor treatment had an incomplete effect. It can be concluded that in the streptozotocin model, hyperglycemia is followed by an early macrophage recruitment that contributes to the molecular and structural events that could lead to glomerulosclerosis. Therefore, besides direct stimulation of mesangial cells by hyperglycemia, macrophages recruited in the glomeruli during the early phase of hyperglycemia could secondarily act on mesangial cells.
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PMID:Early glomerular macrophage recruitment in streptozotocin-induced diabetic rats. 1086 70

To investigate the tropism of the T-lymphotropic human herpesvirus 7 (HHV-7) for hematopoietic progenitors, cord blood CD34(+) cells were inoculated in vitro with HHV-7 and then induced to differentiate along the granulocytic and erythroid lineages by the addition of appropriate cytokine cocktails. In semisolid assays, HHV-7 modestly affected the growth of committed (granulocytic/macrophagic and erythroid) progenitors, whereas it significantly decreased the number of pluripotent (granulocytic/erythroid/ monocytic/megakaryocytic) progenitors. Such inhibitory effect was completely abrogated by incubating HHV-7 inoculum with anti-HHV-7 neutralizing serum. In liquid cultures, HHV-7 hastened maturation along the myeloid but not the erythroid lineage, as demonstrated by the up-regulation of CD33 early myeloid antigen at day 7 of culture, and of CD15 and CD14 antigens at day 15. Moreover, HHV-7 messenger RNA was detected by reverse transcriptase-polymerase chain reaction (RT-PCR) in cells maturating along both the myeloid and the erythroid lineages. To evaluate the relevance of these in vitro findings, the presence of HHV-7 was investigated in bone marrow (BM) unfractionated mononuclear cells (MCs) as well as in purified CD34(+) and CD34(-) cell subsets, obtained from 14 normal adult donors. HHV-7 DNA was detected by DNA-PCR in 4 of 7 BMMC samples, and it was found to be associated with both the CD34(-) (2 of 7) and the CD34(+ )(1 of 7) fractions. These data indicate that HHV-7 infects BM cells in vivo and shows the ability to affect the survival/differentiation of CD34(+) hematopoietic progenitors in vitro by inhibiting more ancestral progenitors and perturbing the maturation of myeloid cells.
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PMID:Infection of CD34(+) hematopoietic progenitor cells by human herpesvirus 7 (HHV-7). 1089 40

Bacterial lipopolysaccharide (LPS, endotoxin) is a ubiquitous component of dust and air pollution and is suspected to contribute after inhalation to an activation of eosinophils in bronchial tissues of asthmatic patients, provoking inflammatory and allergic processes. We were therefore interested in the interaction of eosinophil granulocytes with LPS and have examined the activation of and uptake to human peripheral blood eosinophils by LPS. Eosinophils were stimulated by LPS and the endotoxic component lipid A and the release of tumor necrosis factor alpha (TNF-alpha) and of the eosinophil-specific granule protein eosinophil cationic protein (ECP) was estimated. The results show induction of TNF-alpha and ECP-release by LPS and lipid A in a dose-dependent manner. Anti-CD14 monoclonal antibody (moAb) (clone MEM-18) and the synthetic lipid A partial structure 406 blocked the release of TNF-alpha and ECP by LPS-stimulated eosinophils. Studies with radioactively labeled LPS showed dose-dependent uptake of (3)H-LPS to eosinophils. The (3)H-LPS uptake was found to be specific because preincubation with unlabeled LPS, compound 406 and also anti-CD14 antibodies inhibited uptake of (3)H-LPS to eosinophil granulocytes. By flow cytometry using anti-CD14 moAb and by reverse transcriptase-polymerase chain reaction (RT-PCR) technique, CD14 expression was detectable. Furthermore, messenger RNA (mRNA) expression of Toll-like receptors (TLR) 2 and TLR 4 was detected, indicating the presence of these CD14 coreceptors. The results indicate that eosinophils can take up LPS and can be stimulated by LPS in a CD14-dependent manner. Hence, in addition to allergens, eosinophils interact with endotoxin, a process that possibly exacerbates ongoing inflammatory and allergic processes.
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PMID:The interaction of human peripheral blood eosinophils with bacterial lipopolysaccharide is CD14 dependent. 1113 66

The recent characterization of human homologues of Toll may be the missing link for the transduction events leading to NF-kappaB activity and proinflammatory gene transcription during innate immune response. Indeed, CD14 is not thought to participate directly in the cell signaling, but rather one or more of the mammalian Toll-like receptors (TLRs) acts in concert with the lipopolysaccharide (LPS) receptor to discriminate between microbial pathogens or their products and initiate transmembrane signaling. Mammalian cells may express as many as 10 distinct TLRs, although the importance of TLR4 in response to gram-negative bacteria and LPS is now supported by the fact that TLR4-mutated mice are LPS resistant. We investigated the expression of TLR4 across the rat brain under basal conditions and in response to systemic LPS and IL-1beta injection. We first cloned the rat TLR4 cDNA via RNA isolation and polymerase chain reaction (PCR) amplification with a proofreading polymerase. Total RNA was isolated from the rat liver tissue using Tri-Reagent and reverse transcribed into cDNA using Superscript II reverse transcriptase and an oligonucleotide primer with a degenerate 3' end of sequence 5'-T12(GAC)N-3'. Positive hybridization signal was found in the leptomeninges, choroid plexus (chp), subfornical organ, organum vasculosum of the lamina terminalis, median eminence, and area postrema. Scattered small cells also displayed a convincing hybridization signal within the brain parenchyma. Few well-defined nuclei exhibited positive TLR4 transcript: the supramamillary nucleus, cochlear nucleus, and the lateral reticular nucleus. The circumventricular organs, the leptomeninges, and chp also exhibited constitutive expression of the LPS receptor mCD14. In contrast to the strong up-regulation of the gene encoding mCD14 during endotoxemia, neither LPS nor IL-1beta caused a convincing increase in the TLR4 mRNA levels across the CNS. A down-regulation of the gene encoding TLR4 was found in the cerebral tissue of immune-challenged animals. The constitutive expression of both mCD14 and TLR4 may explain the innate immune response in the brain, which originates from the structures devoid of blood-brain barrier in presence of circulating LPS.
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PMID:Toll-like receptor 4: the missing link of the cerebral innate immune response triggered by circulating gram-negative bacterial cell wall components. 1114 3

We have shown previously that chitosan-polyvinyl pyrrolidone (PVP) hydrogels are blood compatible, islet compatible, and noncytotoxic to various cell types. Because of these potential applications of chitosan-PVP hydrogel, the present study was designed to investigate its effect on macrophage activation. Macrophages did not adhere to hydrogel in culture but maintained their viability and did not undergo apoptosis as confirmed by trypan blue staining and absence of DNA ladder. Hydrogel leach-out products did not exhibit cytotoxic effects on macrophage functionality at mitochondrial and lysosomal level as confirmed by tetrazolium reduction (MTT) and neutral red uptake (NRU) assay. On exposure to hydrogels, macrophages showed comparable expression of activation markers such as CDllb/CD18 (Mac-1), CD45, and CD14 to those cultured in the presence of PTFE, a known biocompatible control, indicating its nonactivating nature. Macrophage activation was also assessed by checking the level of messenger RNA of inflammatory cytokines such as IL-6 and TNF-alpha by reverse transcriptase polymerase chain reaction (RT-PCR), which did not show stastistically significant difference (p > 0.05) in the expression of these transcripts in both control and hydrogel-exposed macrophages. The nonimmunogenic nature of the hydrogel was further confirmed by the lack of induced proliferation of mouse splenic lymphocytes after exposure to hydrogel leach-outs. All these results point out that chitosan-PVP hydrogel did not activate macrophages and thus is immunocompatible. Our results indicate that this hydrogel could be a potential candidate for transplantation studies by virtue of its biocompatibility and imunocompatibility.
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PMID:Chitosan-polyvinyl pyrrolidone hydrogel does not activate macrophages: potentials for transplantation applications. 1133 34

The nucleoside adenosine has been shown to control the production of proinflammatory molecules through its actions on cell surface purine receptors. Previously, we have reported that the adenosine A1 receptor (A1AR) regulates tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) expression and exhibits diminished function in patients with multiple sclerosis (MS; Mayne et al., Ann Neurol 1999;45:633-639). In the present study, A1AR expression in both brain and peripheral blood mononuclear cells (PBMC) from MS and control groups was characterized by fluorescence-activated cell sorting (FACS), reverse transcriptase-polymerase chain reaction (RT-PCR), and immunohistochemical analyses. FACS analyses of PBMC revealed that A1AR expression was chiefly detectable on CD14-positive cells and was reduced by 53.1% (p < 0.01) in MS patients compared to controls. A1AR mRNA levels were reduced by 43.1% (p < 0.001) in the brains of MS patients compared to patients with other neurological diseases and controls. A1AR protein expression in brain was detected primarily in CD45-positive glial cells and was markedly diminished in MS patients. The analysis of A1AR transcripts in the brain revealed that the A1AR-beta transcript was diminished (49.2%) in MS patients compared to controls (p < 0.002). These results indicate that the A1AR, expressed principally on cells of monocyte/macrophage lineage in both brain and blood, is selectively diminished in MS patients. Reduction of the A1AR-beta transcript in MS patients suggests that dysregulated splicing may influence A1AR protein levels, potentially leading to increased macrophage activation and central nervous system inflammation.
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PMID:Diminished adenosine A1 receptor expression on macrophages in brain and blood of patients with multiple sclerosis. 1135 56

The molecular cloning of the t(5;10)(q33;q22) associated with atypical chronic myeloid leukemia (CML) is reported. Fluorescence in situ hybridization (FISH), Southern blot, and reverse transcriptase- polymerase chain reaction analysis demonstrated that the translocation resulted in an H4/platelet-derived growth factor receptor betaR (PDGFbetaR) fusion transcript that incorporated 5' sequences from H4 fused in frame to 3' PDGFbetaR sequences encoding the transmembrane, WW-like, and tyrosine kinase domains. FISH combined with immunophenotype analysis showed that t(5;10)(q33;q22) was present in CD13(+) and CD14(+) cells but was not observed in CD3(+) or CD19(+) cells. H4 has previously been implicated in pathogenesis of papillary thyroid carcinoma as a fusion partner of RET. The H4/RET fusion incorporates 101 amino acids of H4, predicted to encode a leucine zipper dimerization domain, whereas the H4/PDGFbetaR fusion incorporated an additional 267 amino acids of H4. Retroviral transduction of H4/PDGFbetaR, but not a kinase-inactive mutant, conferred factor-independent growth to Ba/F3 cells and caused a T-cell lymphoblastic lymphoma in a murine bone marrow transplantation assay of transformation. Mutational analysis showed that the amino-terminal H4 leucine zipper domain (amino acids 55-93), as well as H4 amino acids 101 to 386, was required for efficient induction of factor-independent growth of Ba/F3 cells. Tryptophan-to-alanine substitutions in the PDGFbetaR WW-like domain at positions 566/593, or tyrosine-to-phenylalanine substitutions at PDGFbetaR positions 579/581 impaired factor-independent growth of Ba/F3 cells. H4/PDGFbetaR is an oncoprotein expressed in t(5;10)(q33;q22) atypical CML and requires dimerization motifs in the H4 moiety, as well as residues implicated in signal transduction by PDGFbetaR, for efficient induction of factor-independent growth of Ba/F3 cells. (Blood. 2001;97:3910-3918)
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PMID:H4(D10S170), a gene frequently rearranged in papillary thyroid carcinoma, is fused to the platelet-derived growth factor receptor beta gene in atypical chronic myeloid leukemia with t(5;10)(q33;q22). 1138 34


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