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)

Inspection of the intron splice junction of the mouse chemokine receptor fusin/CXC chemokine receptor R-4 (CXCR-4) revealed a potential in-frame alternative splice site in the region encoding the N-terminal ectodomain of the receptor. Both predicted splice products were detected by reverse transcriptase-PCR. Cell lines of T lymphocyte, B lymphocyte, and macrophage lineage, plus populations of elicited peritoneal exudate cells, thymocytes, and astrocytes coexpressed mRNA for both isoforms. The full length cDNA of the shorter alternate splice product, termed CXCR-4B, was cloned from peritoneal exudate cell RNA. Chinese hamster ovary cells transfected with either isoform, CXCR-4A or CXCR-4B, responded to stromal cell-derived factor-1alpha with a rise in intracellular calcium. Both alternate splice products are therefore functional stromal cell-derived factor-1 alpha receptors.
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PMID:Alternate splicing of mouse fusin/CXC chemokine receptor-4: stromal cell-derived factor-1alpha is a ligand for both CXC chemokine receptor-4 isoforms. 910 15

Chemokines are small proteins that selectively activate and recruit leukocytes to sites of inflammation. Several of them, including the CC chemokines RANTES, MIP-1 alpha, MIP-1 beta, MCP-1, and the CXC chemokines IL-8, GRO-alpha, ENA-78 have been identified in rheumatoid synovium, implicating a potential role for these molecules in rheumatoid arthritis. We have investigated the expression patterns of CC chemokine receptors in the joints of mice with collagen-induced arthritis, a model for human rheumatoid arthritis. In addition, we have investigated the incidence and severity of arthritis in mice receiving administration of MetRANTES, a modified chemokine which is a nanomolar antagonist of certain CC chemokine receptors. The mRNA expression pattern of the chemokines and their receptors in the joints of arthritic mice was investigated using reverse transcriptase-PCR and in situ hybridization. An upregulation of the CC chemokine receptors mCCR1, mCCR2; mCCR3 and mCCR5 was found in the joints from arthritic mice, compared to control animals. In addition, injections of MetRANTES reduced the incidence of disease in a dose dependent manner. Furthermore, in MetRANTES-treated mice that did develop arthritis a significantly lower severity of disease was observed compared with control animals. Our data clearly demonstrate a role for CC chemokines and their receptors in inflammatory joint destruction and support the use of chemokine receptor antagonists as potential tools to control inflammatory diseases such as rheumatoid arthritis.
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PMID:Effect of a CC chemokine receptor antagonist on collagen induced arthritis in DBA/1 mice. 923 36

Chemokines play an important role in the regulation of endothelial cell (EC) function, including proliferation, migration and differentiation during angiogenesis, and re-endothelialization after injury. In this study, reverse transcriptase-polymerase chain reaction was used to reveal expression of various CXC and CC chemokine receptors in human umbilical vein EC. Northern analysis showed that CXCR4 was selectively expressed in vascular EC, but not in smooth muscle cells. Compared with other chemokines, stromal cell-derived factor-1alpha (SDF-1alpha), the known CXCR4 ligand, was an efficacious chemoattractant for EC, causing the migration of approximately 40% input cells with an EC50 of 10-20 nM. Of the chemokines tested, only SDF-1alpha induced a rapid, though variable mobilization of intracellular Ca2+ in EC. Experiments with actinomycin D demonstrated that CXCR4 transcripts were short-lived, indicating a rapid mRNA turnover. Interferon-gamma (IFN-gamma) caused a pronounced down-regulation of CXCR4 mRNA in a concentration- and time-dependent manner. In a striking functional correlation, IFN-gamma treatment also attenuated the chemotactic response of EC to SDF-1alpha. IL-1beta, tumor necrosis factor-alpha, and lipopolysaccharide produced a time course-dependent biphasic effect on CXCR4 transcription. Expression of CXCR4 in EC is significant, more so as it and several CC chemokine receptors have been shown to serve as fusion co-receptors along with CD4 during human immunodeficiency virus infection. Taken together, these findings provide evidence of chemokine receptor expression in EC and offer an explanation for the action of chemokines like SDF-1alpha on the vascular endothelium.
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PMID:Chemokine receptors in human endothelial cells. Functional expression of CXCR4 and its transcriptional regulation by inflammatory cytokines. 946 27

Studies on the development and function of CD4+ TH1 and TH2 cells during the progression to AIDS may increase the understanding of AIDS pathogenesis. The preferential replication of human immunodeficiency virus (HIV) in either TH1 or TH2 cells could alter the delicate balance of the immune response. TH1 (gamma interferon [IFN-gamma] positive, interleukin-4 [IL-4] and IL-5 negative) and TH2 (IFN-gamma negative, IL-4 and IL-5 positive) clones, developed from several healthy donors, pedigreed by reverse transcriptase PCR (RT-PCR) and enzyme linked immunosorbent assay have similar levels of cell surface expression of CD4 and several chemokine receptor cofactors necessary for viral entry. After activation by specific antigens and infection with T-cell-tropic strains of HIV type 1 (HIV-1), TH1 and TH2 clones showed similar levels of viral entry and reverse transcription. At days 3 through 14 postinfection, HIV replicated to similar levels in several TH1 and TH2 clones as measured by release of HIV p24 and total number of copies of gag RNA/total cell RNA as measured by RT-PCR. When values were normalized for viable cell number in three clones of each type, there was up to twofold more HIV RNA in TH1 than TH2 cells. In addition, several primary monocytotropic HIV-1 strains were able to replicate to similar levels in TH1 and TH2 cells. These studies suggest that the importance of TH1 and TH2 subsets in AIDS pathogenesis transcends clonal differences in their ability to support HIV replication.
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PMID:Similar levels of human immunodeficiency virus type 1 replication in human TH1 and TH2 clones. 957 96

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

CXCR4 is the receptor for the alpha-chemokine stromal cell-derived factor 1 (SDF-1) and has been shown to be expressed on a diversity of leukocytes. In this report, the expression of the CXCR4 receptor in cells of megakaryocytic lineage and the role of SDF-1 in megakaryocytopoiesis were investigated. Using flow cytometry in combination with reverse transcriptase-polymerase chain reaction (RT-PCR), we observed that bone marrow CD34(+), CD61(+) cells, blood platelets, and megakaryocytic leukemia cell lines all expressed the CXCR4 receptor. To examine the expression of the CXCR4 receptor on megakaryocyte progenitors (colony-forming units-megakaryocyte [CFU-Meg]), CXCR4-positive and -negative CD34(+) populations were separated from bone marrow and cultured in a plasma clot culture system. A subpopulation of the CFU-Meg was found in the CXCR4-positive fraction. The functional significance of CXCR4 expression on cells of the megakaryocytic lineage was examined by studying the effects of SDF-1alpha on migration and proliferation of megakaryocyte progenitor cells in vitro. We found that SDF-1alpha potently induced megakaryocyte progenitor migration and significantly enhanced adhesion of mature marrow megakaryocytes to endothelium. No marked effects of SDF-1alpha alone or in combination with thrombopoietin and stem cell factor/kit ligand on megakaryocyte production in vitro were noted. These results demonstrate for the first time that the CXCR4 alpha-chemokine receptor is expressed on cells of the megakaryocytic lineage from progenitors to platelets and that its ligand SDF-1alpha may modulate several aspects of megakaryocytopoiesis.
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PMID:The alpha-chemokine receptor CXCR4 is expressed on the megakaryocytic lineage from progenitor to platelets and modulates migration and adhesion. 968 Mar 41

Alveolar macrophages (AM) are important host-defense cells and targets of human immunodeficiency virus type 1 (HIV-1) infection. However, the receptors mediating HIV-1 entry into AM are not completely characterized. We observed that, in addition to CD4 receptors, AM from healthy adults expressed low levels of CCR5, CCR3, and CXCR4 chemokine receptors by flow cytometry, and specific messenger RNA was detected for all three receptors by reverse transcriptase/polymerase chain reaction. The macrophage monocytotropic (M-tropic; YU2) and dual-tropic (89.6) HIV-1 env-pseudotypes entered AM efficiently, as expected given CCR3 and CCR5 expression. However, the T-lymphocytotropic (T-tropic; HXB2) pseudotype did not enter AM despite expression of the appropriate chemokine coreceptor CXCR4. Incubation of AM with regulated on activation, normal T cells expressed and secreted (RANTES) significantly impaired entry of the M-tropic (YU2) HIV-1 pseudotype, whereas SDF-1beta or eotaxin did not impair entry. The entry of simian immunodeficiency virus (SIV) pbj1.9 env-pseudotype into AM was not blocked by RANTES, SDF-1beta, or eotaxin. The competence of these chemokine receptors for virus entry was confirmed in Cf2Th canine thymocytes cotransfected with the human CD4 and chemokine receptors. Entry of the M-tropic (YU2) HIV-1 pseudotype was shown to be mediated by either CCR3 or CCR5, the T-tropic (HXB2) HIV-1 pseudotype by CXCR4, and the dual-tropic (89.6) HIV-1 or the SIVpbj1. 9 pseudotype by CCR5, CCR3, or CXCR4. Our data indicate that the mechanisms for HIV-1 entry are both receptor-specific and cell type-specific, and that chemokine receptor expression on AM does not fully explain cell susceptibility to different virus isolates.
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PMID:CD4 receptor-dependent entry of human immunodeficiency virus type-1 env-pseudotypes into CCR5-, CCR3-, and CXCR4-expressing human alveolar macrophages is preferentially mediated by the CCR5 coreceptor. 1022 56

Chemokines are thought to play an important part in the development of inflammation in atopic dermatitis. Eotaxin, a CC chemokine, is a potent chemoattractant and activator of human eosinophils, basophils and Th2 lymphocytes which acts via the chemokine receptor CCR3. We studied the expression of eotaxin and CCR3, as well as MCP-3, MIP-1alpha and interleukin-8, in atopic dermatitis and normal skin by immunohistochemistry and nested reverse transcriptase-polymerase chain reaction. Skin biopsy specimens were obtained from nonlesional and lesional skin of patients with atopic dermatitis and of nonatopic controls. Immunoreactivity and transcripts of eotaxin and CCR3 were significantly increased in lesional skin from atopic dermatitis, but not in nonatopic controls. In nonlesional atopic dermatitis samples CCR3 expression was also significantly increased at the mRNA and protein level, whereas eotaxin was increased at the mRNA level only. No significant difference in the expression of MCP-3, MIP-1alpha, and interleukin-8 was observed between skin samples from atopic dermatitis and nonatopic controls. The enhanced local production of eotaxin may lead to the recruitment of eosinophils and T lymphocytes, which both express CCR3 and contribute to the initiation and maintenance of inflammation.
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PMID:Enhanced expression of eotaxin and CCR3 in atopic dermatitis. 1041 17

Certain chemokines inhibit HIV replication through binding to cell surface receptors which also act as viral coreceptors. Based on our previous observations that HIV-1 Tat can interact with alpha- and beta-chemokine receptors, we investigated the potential effect of extracellular Tat (ecTat) on infection and replication of CCR5-dependent (R5) and CXCR4-using (X4) HIV-1 strains in primary activated peripheral blood mononuclear cells (PBMC) of uninfected donors. Receptor desensitization and binding competition studies were used to determine chemokine receptor binding by ecTat. Standard HIV replication assays based on reverse transcriptase (RT) activity determination in culture supernatants of PBMC and real time PCR for HIV-1 gag DNA were used to determine potential effects on early (entry or RT) steps of infection. ecTat bound to CXCR4 expressing monocytes and mitogen-activated PBMC, and competed with the natural ligand of CXCR4, SDF-1alpha (stromal cell-derived factor-1alpha) in calcium mobilization assays. EcTat inhibited replication of the X4 HIV-1 (LAI/IIIB strain) in activated PBMC at concentrations close to those of SDF-1alpha, whereas it only modestly interfered with R5 HIV-1 (BaL) replication in PBMC. Both SDF-1alpha and ecTat inhibited accumulation of X4 HIV-1 gag DNA, indicating interference with viral entry and/or RT. Our data show the surprising and counter-intuitive observation that ecTat selectively represses X4 HIV replication. This could favour spreading of R5 viruses, a condition observed in vivo immediately after transmission and in the early asymptomatic phase of infection.
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PMID:Inhibition of CXCR4-dependent HIV-1 infection by extracellular HIV-1 Tat. 1077 39

The role of placenta in vertical transmission is not yet fully understood. A protective role of the placenta during gestation is suggested by the finding that caesarian sections reduce the risk of transmission of human immunodeficiency virus (HIV)-1 from mother to child three- to fourfold. Here we investigated whether the immunological milieu of the placenta might be important in HIV-1 transmission. In situ imaging of immunohistochemically stained placenta sections and reverse transcriptase-polymerase chain reaction demonstrated a fourfold increase in CCR5:CXCR4 expression ratio in placentae from transmitting women compared to placentae from nontransmitting women. This chemokine receptor repertoire was consistent with an up-regulation of interleukin-4 and interleukin-10 expression in placentae from nontransmitting placentae compared to transmitting placentae. In situ imaging demonstrated that CCR5 and CXCR4 were expressed on placental macrophages and lymphocytes but not in trophoblasts. Simultaneous immunofluorescence/ultrasensitive in situ hybridization for HIV-1 gag-pol mRNA revealed that HIV-1 infects primarily CXCR4-expressing cells in placentae from nontransmitting women whereas predominantly CCR5-expressing cells were infected in placentae from transmitting women. These data are consistent with transmission of a homogeneous population of nonsyncytium-inducing HIV-1 isolates that use CCR5 as co-receptor.
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PMID:Up-regulation of CCR5 expression in the placenta is associated with human immunodeficiency virus-1 vertical transmission. 1110 53


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