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)

CGN is a rapidly progressive glomerular disease. Monocytes/macrophages are frequently observed in glomeruli in cases of CGN and they are considered to play a crucial role in the pathogenesis of this disease. We described previously the glomerular expression of monocyte chemoattractant protein-1 (MCP-1), which is a potent chemoattractant for monocytes and a member of CC chemokine family, in an experimental model of CGN. In the present study we investigated the expression of mRNAs for other CC chemokines, namely, MCP-3, macrophage inflammatory protein-1alpha (MIP-1alpha), MIP-1beta, RANTES and TCA3, all of which are chemotactic for monocytes, in the CGN model. First, we established a reverse transcriptase-polymerase chain reaction (RT-PCR) method by which mRNA for each of the CC chemokines could be amplified separately, and then we measured the levels of the expression of mRNAs for the chemokines in diseased glomeruli at several time points after induction of CGN. The mRNAs for all CC chemokines examined were expressed in glomeruli of rats with CGN. Moreover, induction of the gene expression of MIP-1alpha and MIP-1beta seemed to occur earlier than that of the others. CC chemokines may contribute to the recruitment and activation of monocytes in CGN, and each individual CC chemokine may play an overlapping but distinct role in the pathogenesis of this disease.
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PMID:Gene expression of CC chemokines in experimental crescentic glomerulonephritis (CGN). 921 37

Recent data suggest that mast cells (MC) are involved in the regulation of leukocyte accumulation in inflammatory reactions. In this study, expression of leukocyte-chemotactic peptides (chemokines) in purified human lung MC (n = 16) and a human mast cell line, HMC-1, was analyzed. Northern blotting and reverse transcriptase-polymerase chain reaction (RT-PCR) showed baseline expression of monocyte chemoattractant protein (MCP)-1 mRNA in unstimulated MC. Exposure of MC to recombinant stem cell factor (rhSCF, 100 ng/mL) or anti-IgE (10 microgram/mL) was followed by a substantial increase in expression of MCP-1 mRNA. Neither unstimulated nor stem cell factor (SCF )-stimulated lung MC expressed transcripts for interleukin-8 (IL-8), macrophage inflammatory protein-1alpha (MIP-1alpha), MIP-1beta, or RANTES by Northern blotting. The mast cell line HMC-1, which contains a mutated and intrinsically activated SCF-receptor, was found to express high levels of MCP-1 mRNA in a constitutive manner. Exposure of HMC-1 cells to rhSCF resulted in upregulation of MCP-1 mRNA expression, and de novo expression of MIP-1beta mRNA. The SCF-induced upregulation of MCP-1 mRNA in lung MC and HMC-1 was accompanied by an increase in immunologically detectable MCP-1 in cell supernatants (sup) (lung MC [<98%], control medium, 1 hour: 159 +/- 27 v SCF, 100 ng/mL, 1 hour: 398 +/- 46 pg/mL/10(6) cells; HMC-1: control, 1 hour: 894 +/- 116 v SCF, 1 hour: 1,536 +/- 265 pg/mL/10(6)). IgE-dependent activation was also followed by MCP-1 release from MC. MC-sup and HMC-1-sup induced chemotaxis in blood monocytes (Mo) (control: 100% +/- 12% v 2-hour-MC-sup: 463% +/- 38% v HMC-1-sup: 532% +/- 12%), and a monoclonal antibody (MoAb) to MCP-1 (but not MoAb to IL-8) inhibited Mo-chemotaxis induced by MC-sup or HMC-1-sup (39% to 55% inhibition, P < .05). In summary, our study identifies MCP-1 as the predominant CC-chemokine produced and released in human lung MC. MCP-1 may be a crucial mediator in inflammatory reactions associated with MC activation and accumulation of MCP-1-responsive leukocytes.
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PMID:The c-kit ligand stem cell factor and anti-IgE promote expression of monocyte chemoattractant protein-1 in human lung mast cells. 937 54

Chemokine receptors play a crucial role in the recruitment of immune cells to sites of inflammation. Although chronic diseases of the brain are often accompanied by inflammatory events, there is presently no information about the occurrence and regulation of these receptors in the central nervous system (CNS). Moreover, one CC-chemokine receptor, CKR5, has recently been identified as coreceptor for HIV-1 entry into macrophages. HIV-1 target cells in brain are macrophage-related microglia, which suggests that they are infected by the same mechanism (He et al.,: Nature 385:645-649, 1997). Although rats are not susceptible to HIV-1 infection, they can be used to study chemokine receptor regulation in a variety of brain pathologies. After cloning CC-CKR5 and establishing reverse transcriptase polymerase chain reaction (RT-PCR) for its ligands macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and regulated on activation, normal T cell-expressed and secreted (RANTES), we studied expression of these four mRNAs in purified microglia and compared it with their expression in rat brain. Lipopolysaccharide (LPS)-treated microglia showed transiently increased mRNA levels of both CKR5 and its ligands. Similar data were obtained from brains of LPS-injected rats. In middle cerebral artery occluded (MCAO)-animals, RANTES mRNA was unaffected, whereas CKR5 mRNA showed a sustained rise until 96 hr after surgery. MIPs exogenously added to microglial cultures markedly reduced CKR5 mRNA expression, whereas RANTES did not. MIP mRNAs, in contrast to RANTES and CKR5 mRNAs, were undetectable in normal brain. RANTES appears to play a role distinct from MIPs in brain. In summary, upregulation of CC-chemokines and CKR5 in the CNS upon bacterial infection or in ischemia may impact on microglial activation stage and result in increased risk of HIV-1 infection.
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PMID:Cloning of rat HIV-1-chemokine coreceptor CKR5 from microglia and upregulation of its mRNA in ischemic and endotoxinemic rat brain. 967 Sep 89

We have recently demonstrated that IL-12 induced cellular inflammatory responses consisting mainly of accumulation of mononuclear leucocytes in the lungs of mice infected with Cryptococcus neoformans and protected mice against fulminant infection. We examined the involvement of endogenously synthesized IFN-gamma in such a response by investigating the effects of a neutralizing monoclonal antibody against this cytokine. The latter treatment completely abrogated the positive effects of IL-12 on survival of infected mice and prevented IL-12-induced elimination of microbials from the lungs. Histopathological examination showed that accumulation of mononuclear leucocytes in the infected lungs caused by IL-12 was clearly inhibited by anti-IFN-gamma MoAb. We also examined the local production of mononuclear cell-attracting chemokines such as monocyte chemotactic protein-1 (MCP-1), regulated upon activation, normal T cell expressed and secreted (RANTES), macrophage inflammatory protein-1alpha (MIP-1alpha), MIP-1beta and IFN-gamma-inducible protein 10 (IP-10) in the lungs using a reverse transcriptase-polymerase chain reaction (RT-PCR) method. We found that these chemokines were not synthesized in the infected lungs, while IL-12 treatment markedly induced their production. Interestingly, neutralizing anti-IFN-gamma MoAb strongly suppressed IL-12-induced production of these chemokines. Similar results were obtained with MCP-1 and MIP-1alpha when their synthesis was measured at the protein level using respective ELISA kits. Our results indicate that IFN-gamma plays a central role in the protective effects of IL-12 by inducing mononuclear leucocyte-attracting chemokines and cellular inflammatory responses.
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PMID:Interferon-gamma (IFN-gamma)-dependent protection and synthesis of chemoattractants for mononuclear leucocytes caused by IL-12 in the lungs of mice infected with Cryptococcus neoformans. 1040 24

Recruitment of inflammatory cells is of critical importance in the pathogenesis of immune-mediated demyelinating diseases in the peripheral nervous system (PNS). Evidence is increasing that chemokines might play a key role in this process, since they promote leukocyte entry into the nervous system during immune-mediated inflammation. In the present study we report the expression pattern of the chemokines interferon-gamma-inducible protein (IP)-10, monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and regulated upon activation normal T cell expressed and secreted (RANTES) in sciatic nerves from animals with myelin-induced experimental autoimmune neuritis, using a semiquantitative reverse transcriptase-PCR dot-blot hybridization assay. The mRNAs for MIP-1alpha and MIP-1beta were found to be upregulated with peak values at day 13 post-immunization (p.i.), preceding maximum disease severity. In contrast, mRNAs for MCP-1, RANTES, and IP-10 exhibited peak levels coincident with peak of the disease at day 15 p.i. Increased mRNA expression was associated with enhanced protein levels, as demonstrated by immunoblotting for each chemokine investigated. Immunohistochemistry for IP-10 protein revealed immunoreactivity associated with perineurial endothelial cells. RANTES protein was localized immunohistologically to invading T lymphocytes. Our findings suggest that chemokines, which act towards T cells and mononuclear phagocytes, are sequentially upregulated during the clinical course of EAN and thus may contribute to the pathogenesis of inflammatory demyelinating diseases of the PNS.
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PMID:Sequential expression of chemokines in experimental autoimmune neuritis. 1102 41

MS is a demyelinating disease characterized by infiltration of monocytes and lymphocytes into the brain parenchyma, destruction of oligodendrocytes and loss of myelin. Since chemokines play a major role in the migration of monocytes and T cells, we here investigated the expression of the CC chemokines MIP-1alpha, MIP-1beta, and RANTES in brain tissue from MS patients using reverse transcriptase-polymerase chain reaction techniques. Both MIP-1beta as well as RANTES were found to be significantly elevated in brain tissue of MS patients. In addition, MIP-1alpha was also increased, although not significantly. Immunohistochemistry revealed that, whereas RANTES was mainly localized in reactive astrocytes, MIP-1alpha and MIP-1beta immunoreactivity was predominantly found in perivascular and parenchymal macrophages, containing myelin degradation products. Thus, chemokines appear to be associated with MS and an increased chemokine expression may further enhance disease progression by attracting more leucocytes into the brain parenchyma and by activation of effector functions of astrocytes and microglial cells.
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PMID:Macrophage inflammatory protein-1alpha (MIP-1alpha), MIP-1beta, and RANTES mRNA semiquantification and protein expression in active demyelinating multiple sclerosis (MS) lesions. 1109 Dec 83

The chemokine receptors CXCR4 and CCR5 are used as co-receptors by the T cell-tropic (X4) and macrophage-tropic (R5) HIV-1 strains, respectively, for entering their host cells. Viral entry can be inhibited by the natural ligands for CXCR4, the CXC chemokine SDF-1 and CCR5, the CC chemokines RANTES, MIP-1alpha and MIP-1beta. Several peptidic compounds, T22 (an 18-mer), T134 (a 14-mer), ALX40-4C (a 9-mer) and CGP 64222 (also a 9-mer), have been identified as CXCR4 antagonists and show anti-HIV activity. Also, the HIV-1 tat protein has been described as a 'natural' CXCR4 antagonist with anti-HIV-1 activity. The most potent and specific CXCR4 antagonists are the bicyclam derivatives, which also potently block X4 HIV replication. AMD3100 has proved to be a highly specific CXCR4 antagonist, which consistently blocks the outgrowth of all X4 HIV and dual-tropic (R5/X4) variants that use CXCR4 for entering the cells (cell lines, CXCR4-transfected cell lines, lymphocytes or monocytes/ macrophages). From the bicyclam analogues, AMD3100 was selected as the clinical drug candidate, which, after initial Phase I (safety) studies, has proceeded to Phase II (efficacy) trials. The first non-peptidic compound that interacts with CCR5, and not with CXCR4, is a quaternary ammonium derivative, called TAK-779, which also has potent but variable anti-HIV activity. We believe that HIV entry/fusion inhibitors will become important new antiviral agents to combat AIDS. However, like the current clinically approved agents, they will need to be used in combinations consisting of antivirals that target other aspects of the HIV replication cycle, such as reverse transcriptase and protease, to obtain optimum therapeutic effects.
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PMID:Inhibition of HIV infection by CXCR4 and CCR5 chemokine receptor antagonists. 1159 85

Interleukin-16 (IL-16) and the beta-chemokines (RANTES, monocyte chemotactic protein-1 (MCP-1), macrophage inhibitory protein (MIP)-1alpha and (MIP)-1beta) are soluble in vitro suppressors of macrophage tropic HIV-1 strains. The reduction of HIV-1 RNA plasma levels in late-stage patients receiving protease inhibitors has been associated with increased concentrations of MIP-1alpha, MIP-1beta, RANTES and IL-16 and a decrease in levels of MCP-1. We determined plasma levels of MCP-1, MIP-1alpha, MIP-1beta, RANTES and IL-16 during the first 16 weeks of highly active antiretroviral therapy (HAART) in chronic HIV-1-infected patients. Patients were administered one of two therapeutic regimens based on either a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI). No differences were seen in the levels of RANTES and IL-16 over the first 16 weeks of HAART in either treatment group. MCP-1 decreased significantly in the PI-treated group over the first 16 weeks of HAART (P = 0.0003). A significant increase was observed in the levels of MIP-1alpha and MIP-1beta in the NNRTI cohort (P = 0.0010 and P = 0.0012, respectively). A significant decrease in levels of MIP-1alpha and MIP-1beta (P = 0.0015 and P = 0.0299, respectively) was observed over the 16 weeks in the PI cohort. A significant difference was seen when the levels of MIP-1alpha and MIP-1beta were compared between the NNRTI and the PI cohorts at week 16 (P = 0.04 and P = 0.05, respectively). Evaluation of CCR5 expression ex vivo revealed no difference between the two treatment groups. Patients were genotyped for CCR5 Delta32 and the incidence of heterozygosity was lower than in the HIV-1 seronegative controls (3% compared to 19%).
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PMID:Impact of NNRTI compared to PI-based highly active antiretroviral therapy on CCR5 receptor expression, beta-chemokines and IL-16 secretion in HIV-1 infection. 1239 Mar 2

HIV entry within the cell involves the presence of at least two chemokine co-receptors, the CCR5 and CXCR4 receptors. Viral entry can be inhibited by the natural ligands for CXCR4, the CXC chemokine SDF-1 and CCR5, the CC chemokines RANTES, MIP-1alpha and MIP-1beta, respectively. Much research has been devoted ultimately to the development of small molecule chemokine antagonists that inhibit virus entry within the cell, and constitute in this way novel antiviral medications. The most potent and specific CXCR4 antagonists reported up to now are the bicyclam derivatives, which also potently block X4 HIV replication. One such compound, AMD3100 has proved to be a highly specific CXCR4 antagonist, which consistently blocks the outgrowth of all X4 HIV and dual-tropic (R5/X4) variants that use CXCR4 for entering the cells. From such bicyclam analogues, AMD3100 was selected as the clinical candidate, which, after initial Phase I studies, proceeded to Phase II trials, but unfortunately showed significant cardiac side effects which lead to its withdrawal from further development. The first nonpeptidic compound that interacts with CCR5, but not with CXCR4, is a quaternary ammonium derivative, TAK-779, which also shows potent but variable anti-HIV activity. A large number of potent CCR5 antagonists from several classes of polycyclic derivatives have been recently disclosed. Many such derivatives showed nanomolar binding affinity to the receptor, and at least one of them, the oxime-piperidine derivative SCH-351125 has progressed to clinical evaluation. The development of such agents for clinical use may constitute an additional approach for the treatment of HIV infection, in addition to the classical one involving reverse transcriptase and protease inhibitors.
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PMID:Non-peptidic chemokine receptors antagonists as emerging anti-HIV agents. 1242 Jul 52

The expression of chemokines and chemokine receptors was studied in Leishmania donovani (LD)-infected human mononuclear phagocytes and the human monocytic cell line THP1. Our studies showed that LD infection caused the upregulation of three beta chemokines (macrophage inflammatory protein-1 alpha (MIP-1alpha), MIP-1beta and RANTES (regulated on activation normal T cell expressed and secreted)), one alpha chemokine (interleukin-8 (IL-8)) and the CC chemokine receptor 5 (CCR5) but not CCR1, as evident from reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. The CCR5 upregulation in human mononuclear phagocytes and THP1 cells was also evident by confocal microscopy. The possible association of such upregulation in relation to Leishmania and human immunodeficiency virus (HIV) coinfection was discussed.
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PMID:Infection of human mononuclear phagocytes and macrophage-like THP1 cells with Leishmania donovani results in modulation of expression of a subset of chemokines and a chemokine receptor. 1266


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