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:3.1.27.1 (RNase)
16,360 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Using flow cytometric and RNase protection assays, this study examined the expression of chemokine receptors in nonactivated natural killer (NK) cells and compared this expression with NK cells activated with interleukin (IL)-2, which either adhered to plastic flasks (AD) or did not adhere (NA). None of the NK cell subsets expressed CXCR2, CXCR5, or CCR5. The major differences between these cells include increased expression of CXCR1, CCR1, CCR2, CCR4, CCR8, and CX(3)CR1 in AD when compared to NA or nonactivated NK cells. The chemotactic response to the CXC and CC chemokines correlated with the receptor expression except that all 3 populations responded to GRO-alpha, despite their lack of CXCR2 expression. Pretreatment of these cells with anti-CXCR2 did not inhibit the chemotactic response to GRO-alpha. In addition, nonactivated and NA cells responded to fractalkine, although they lack the expression of CX(3)CR1. This activity was not inhibited by anti-CX(3)CR1. Viral macrophage inflammatory protein (vMIP)-I, I-309, and TARC competed with the binding of (125)I-309 to AD cells with varying affinities. Transforming growth factor (TGF)-beta1 but not any other cytokine or chemokine examined including interferon (IFN)-gamma, MIP-3beta, macrophage-derived chemokine (MDC), thymus and activation-regulated chemokine (TARC) or I-309, up-regulated the expression of CXCR3 and CXCR4 on NK cell surface. This is correlated with increased chemotaxis of NK cells treated with TGF-beta1 toward stromal cell-derived factor (SDF)-1alpha and interferon-inducible protein-10 (IP-10). Messenger RNA for lymphotactin, RANTES, MIP-1alpha, and MIP-1beta, but not IP-10, monocyte chemotactic protein (MCP)-1, IL-8, or I-309 was expressed in all 3 NK cell subsets. Our results may have implications for the dissemination of NK cells at the sites of tumor growth or viral replication. (Blood. 2001;97:367-375)
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PMID:Expression and regulation of chemokine receptors in human natural killer cells. 1115 10

Infiltration of renal allografts by leukocytes is a hallmark of acute transplant rejection. Chemokines attract leukocytes bearing specific chemokine receptors, and the specific leukocyte chemokine receptor phenotype is associated with types of immune responses, ie, T helper subtype 1 (Th1; CXC chemokine receptor 3 [CXCR3], CC chemokine receptor 5 [CCR5]) versus Th2 (CCR3, CCR4, CCR8). We studied the expression of the chemokine monocyte chemoattractant protein-1 and the chemokine receptors CCR2B and CXCR4 messenger RNA (mRNA) by in situ hybridization, as well as the chemokine receptors Duffy antigen receptor for chemokines (DARC) and CCR5 protein by immunohistochemistry in renal biopsy specimens with acute cellular rejection (n = 12) and acute vascular rejection (n = 8), transplant nephrectomy specimens (n = 6), and normal areas of tumor nephrectomy specimens (n = 5). CC chemokines and CC chemokine receptor mRNA expression were evaluated by ribonuclease protection assay in specimens from four transplant nephrectomies and one tumor nephrectomy. Upregulation of mRNAs for the chemokines, interferon-inducible protein-10 (IP-10); regulated on activation normal T-cell expressed and secreted; macrophage inflammatory protein-1alpha (MIP-1alpha); MIP-1beta; and lymphotactin, as well as the chemokine receptors, CCR2 and CCR5, were documented during allograft rejection. CCR1 mRNA was detectable in both allografts and controls, but CCR3 and CCR8 were absent. The number of CXCR4, CCR5, and CCR2B mRNAs expressing leukocytes and DARC-positive vessels increased during rejection episodes. CXCR4 mRNA was the most widely expressed. Leukocytes in diffuse interstitial infiltrates were mainly CCR5 positive, but in areas in which leukocytes formed nodular aggregates of infiltrating cells, the number of CCR5-positive cells was low. Instead, leukocytes in these nodular aggregates mainly expressed CXCR4. DARC was expressed on peritubular capillaries, where it was upregulated in areas of interstitial infiltration. Induction of chemokines during renal allograft rejection is accompanied by infiltration of leukocytes bearing the respective chemokine receptors. The upregulation of the CXCR3 ligand IP-10, as well as CCR5 and its ligands, in the absence of CCR3 and CCR8 is indicative that renal allograft rejection is primarily the result of a Th1-type immune response.
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PMID:Expression of chemokines and chemokine receptors during human renal transplant rejection. 1122 76

Lupus nephritis is characterized by immune complex deposition and inflammatory cell infiltration. Therefore, the initiation and progression of lupus nephritis in MRL/MpJ Fas(lpr/lpr) (MRL/lpr) mice were investigated, with a focus on the expression of several chemokines and chemokine receptors. Mice were monitored for proteinuria from 6 to 20 wk of age, and kidneys were examined every 2 wk by light microscopy, electron microscopy, and immunohistologic analyses. Furthermore, the expression of chemokines, chemokine receptors, and proinflammatory cytokines was analyzed in ribonuclease protection assays. MRL/lpr mice demonstrated increased expression of monocyte chemoattractant protein-1, regulated upon activation, normal T cell-expressed and -secreted protein, inducible protein of 10 kD, and macrophage inflammatory protein-1beta at week 8. At that time point, levels of circulating and glomerular immune complexes were increased, and no proteinuria or histopathologic signs of renal damage could be observed. As assessed in immunohistochemical and in situ hybridization analyses, monocyte chemoattractant protein-1 and regulated upon activation, normal T cell-expressed and -secreted protein expression was preferentially located in the glomeruli and interstitium. Mononuclear cell infiltration of the kidney was observed by weeks 10 to 12. At week 12, the renal expression of chemokine receptor 1 (CCR1), CCR2, and CCR5 was increased, mice became proteinuric, and renal damage was histologically evident. Finally, the expression of proinflammatory cytokines was detected (weeks 12 to 14). In summary, (1) chemokines are upregulated before inflammatory cell infiltration, proteinuria, and kidney damage are observed; (2) chemokine generation is restricted to sites of subsequent inflammatory cell infiltration, i.e., glomeruli and interstitium; (3) chemokine receptor expression parallels mononuclear cell infiltration; and (4) proinflammatory cytokines are upregulated later, in parallel with inflammatory cell infiltration and the onset of proteinuria. These results support the hypothesis that chemokines initiate leukocyte infiltration and precede proteinuria and renal damage in MRL/lpr mice.
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PMID:Chemokine expression precedes inflammatory cell infiltration and chemokine receptor and cytokine expression during the initiation of murine lupus nephritis. 1142 66

Murine gammaherpesvirus 68 replicates in the alveolar epithelium and induces an inflammatory infiltrate in the lung, following intranasal challenge, and is cleared 10 and 13 days after infection by a T-cell-dependent mechanism. In order to understand the development of the immune response to this virus and how leukocyte trafficking to the lung is regulated, chemokine expression during MHV-68 infection was examined in lung tissue using an RNase protection assay. Expression of RANTES, eotaxin, MIP-1 alpha, MIP-1 beta, IP-10, and MCP-1 was upregulated by day 7 after infection. Chemokine concentrations in lung lavage fluid were also determined by ELISA. MCP-1, RANTES, MIP-1 alpha, eotaxin, and KC were upregulated during MHV-68 infection. Most of these chemokines have been reported to be chemoattractants for either activated T cells or monocytes, which are the major cellular components of the inflammatory infiltrate induced by the virus. Upregulated expression of the corresponding receptors for the chemokines, including CCR1, CCR2, CCR3, CCR5, and CXCR3, coincided with the development of the inflammatory infiltrate. The chemokine levels peaked at around day 7 after infection, coinciding with peak viral titers and slightly preceding maximal T cell infiltration. In vitro chemotaxis assays confirmed that lung lavage fluid from MHV-68-infected mice had chemotactic activity, which was partially blocked by antibodies to IP-10 and RANTES. These observations suggest that the chemokines detected play an important role in regulating leukocyte trafficking to the lungs during MHV-68 infection.
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PMID:Chemokine induction and leukocyte trafficking to the lungs during murine gammaherpesvirus 68 (MHV-68) infection. 1185 99

Chemokines are small chemoattractant cytokines which participate in the migration of immune cells into the CNS and contribute to the T cell-mediated pathogenesis of multiple sclerosis (MS). The expression of chemokines and their receptors in freshly isolated mononuclear cells from peripheral blood (PBMC) was studied in relation to MS subtype, disease duration and progression in a total of 57 patients with MS (22 relapsing remitting, RRMS; 21 secondary progressive, SPMS; 14 primary progressive, PPMS) and 17 healthy controls. The RNA expression of CCR5 in PBMC was analysed by reverse transcription polymerase chain reaction (RT-PCR) using specific oligonucleotide primers. The PBMC levels of CCR5-ligands MIP-1 alpha/beta and RANTES, and chemokines MCP-1, IL-8, lymphotactin, IP-10 and I-309 were analysed by ribonuclease protection assay (RPA). Significantly increased intracellular CCR5 RNA expression intensity was detected in PPMS when compared with SPMS ( p=0.009), RRMS ( p=0.013), and controls ( p=0.023). However, the surface expression of CCR5 on CD4(+) cells from PBMC, analysed by flow cytometry, appeared to be similar in all MS subtypes and controls. The CCR5-ligands RANTES and MIP-1b were expressed constitutively in all patients and controls. Interleukin-8 was found in all MS subtypes and controls, but IP-10 was detected only in RRMS and SPMS, and lymphotactin occasionally in other subtypes but PPMS. MCP-1, MIP-1a or I-309 were not expressed in any of the groups studied. A correlation was found between the RNA levels of RANTES and CCR5 in PPMS ( r=0.735). Differential profile in the expression of CCR5 and chemokines between PPMS and other MS subtypes may contribute to differences in the pathogenesis of MS and thus can be of importance in the development of new treatments for MS.
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PMID:Differential intracellular expression of CCR5 and chemokines in multiple sclerosis subtypes. 1202 48

The inflammatory response initiated after spinal cord injury (SCI) is characterized by the accumulation of macrophages at the impact site. Monocyte chemoattractant protein-1 (MCP-1) is a strong candidate for mediating chemotaxis of monocytes to the injured nervous system. To help in defining the role of MCP-1 in inflammation after SCI, we evaluated the time course of macrophage accumulation for 2 weeks following a midthoracic spinal cord contusion injury in mice lacking CCR2, a principal receptor for MCP-1. Mice with a deletion of CCR2 resulted in significantly reduced Mac-1 immunoreactivity restricted to the lesion epicenter at 7 days postinjury. The regions devoid of Mac-1 immunoreactivity corresponded to areas of reduced myelin degradation at this time. By 14 days postinjury, however, there were no differences in Mac-1 staining between CCR2 (+/+) and CCR2 (-/-) mice. Analyses of mRNA levels by RNase protection assay (RPA) revealed increases in MCP-1 as well as MCP-3 and MIP-2 mRNA at 1 day postinjury compared with 7 day postinjury. There were no differences in chemokine expression between CCR2-deficient mice and wild-type littermate controls. The CCR2-deficient mice also exhibited reduced expression of mRNA for chemokine receptors CCR1 and CCR5. Together, these results indicate that chemokines acting through CCR2 contribute to the early recruitment of monocytes to the lesion epicenter following SCI.
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PMID:Monocyte recruitment and myelin removal are delayed following spinal cord injury in mice with CCR2 chemokine receptor deletion. 1211 30

Tissue expression of CC and CXC chemokines and chemokine receptors was investigated in 6 cases of classic non-AIDS Kaposi sarcoma (KS) using immunohistochemistry and RNase protection assay (RPA). Immunostaining of frozen sections of KS skin biopsies revealed that KS spindle cells express several chemokine receptors. In KS nodules, almost all KS spindle cells were intensely stained for CXCR4 and CCR5. Other chemokine receptors as CCR1, CXCR3, and CCR2 were also detected in the large majority of KS spindle cells. A minority of KS spindle cells also expressed the fractalkine receptor (FK-R) CX3CR1. The immunohistochemical findings were confirmed at RNA level. In fact, the RNase protection assay (RPA) revealed in 6 of 6 cases the presence of consistent amounts of mRNAs for CXCR4 and CCR1 and in 5 of 6 cases also for CCR5 and CXCR3. Expression of chemokine receptors by KS cells was associated with chemokine production within the lesions. In the same cases, RPA demonstrated the presence of mRNAs for MCP-1, RANTES, IP-10, MIP-1alpha, and MIP-1beta. Chemokine-producing cells, as detected by immunohistochemistry, were mainly spindle-shaped cells resembling tissue macrophages outside KS lesions and some scattered cells (<5%) present within KS nodules. The demonstration of chemokine receptors in KS cells raises the possibility that recruitment of KS cells in response to locally produced chemotactic stimuli may be one of the events involved in the pathogenesis of Kaposi sarcoma.
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PMID:In situ study of chemokine and chemokine-receptor expression in Kaposi sarcoma. 1450 Dec 86

Influenza A virus replicates in the respiratory epithelium and induces an inflammatory infiltrate comprised of mononuclear cells and neutrophils. To understand the development of the cell-mediated immune response to influenza and how leukocyte trafficking to sites of inflammation is regulated, we examined the chemokine expression pattern in lung tissue from A/PR/8/34-infected C57BL/6 mice using an RNase protection assay. Monocyte chemoattractant protein 1, macrophage inflammatory protein 1alpha (MIP-1alpha), MIP-1beta, MIP-3alpha, regulated on activation, normal T expressed and secreted (RANTES), MIP-2, and interferon-inducible protein 10 (IP-10) mRNA expression was up-regulated between days 5 and 15 after infection, consistent with a role for these chemokines in leukocyte recruitment to the lung. Low levels of expression were detected for the CC chemokine receptors (CCR)2 and CCR5, whereas CXC chemokine receptor (CXCR)3 was significantly up-regulated by day 10 after infection, coinciding with peak inflammatory cell infiltration in the airways. As RANTES, IP-10, and their receptors were up-regulated during influenza virus infection, we investigated leukocyte recruitment and viral clearance in mice deficient in RANTES or CXCR3, the receptor for IP-10. Leukocyte recruitment and viral replication in influenza-infected RANTES knockout(-/-) mice were similar to that in control mice, showing that RANTES is not essential for the immune response to influenza infection. Similarly, leukocyte recruitment and viral replication in CXCR3-/- mice were identical to control mice, except at day 8 postinfection, where fewer lymphocytes, neutrophils, and eosinophils were detected in the bronchoalveolar lavage of CXCR3-/- mice. These studies suggest that although the chemokines detected may play a role in regulating leukocyte trafficking to the lung during influenza infection, some may be functionally redundant.
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PMID:Chemokine expression during the development and resolution of a pulmonary leukocyte response to influenza A virus infection in mice. 1524 Jul 57

The majority of HIV-1-infected neonates and infants have a higher level of viremia and develop AIDS more rapidly than infected adults, including differences seen in clinical manifestations. To determine the mechanisms of HIV-1 infection in neonates vs. adults, we compared the replication kinetics of HIV-1 in neonatal (cord) and adult blood T lymphocytes and monocyte-derived macrophages (MDM) from seven different donors. We found that HIV-1 replicated 3-fold better in cord blood T lymphocytes compared with adult blood T lymphocytes and 9-fold better in cord MDM than adult MDM. We also show that this differential HIV-1 replication did not depend on differences in cell proliferative capabilities, cell surface expression of CD4, CXCR4, and CCR5, or in the amount of PCR products of reverse transcription, DNA synthesis, and translocation of preintegration complex into the nucleus in cord and adult T lymphocytes and MDM. Furthermore, using a single-cycle replication competent HIV-1-NL4-3-Env(-) luciferase amphotropic virus, which measures HIV-1 transcriptional activity independent of receptor and coreceptor expression, we found there was a 3-fold increase of HIV-1 LTR-driven luciferase expression in cord T lymphocytes compared with adult T lymphocytes and 10-fold in cord MDM than in adult MDM. The HIV-1 LTR-driven luciferase expression correlated with HIV-1 LTR transcription, as measured by ribonuclease protection assay. These data suggest that the increased replication of HIV-1 in cord blood compared with adult blood mononuclear cells is regulated at the level of HIV-1 gene expression, resulting in a higher level of viremia and faster disease progression in neonates than adults.
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PMID:Differential HIV-1 replication in neonatal and adult blood mononuclear cells is influenced at the level of HIV-1 gene expression. 1686 88

Synthetic siRNA has been considered as a highly promising therapeutic agent for human diseases. However, clinical use of siRNA has been hampered by instability in the body and inability to deliver sufficient RNA interference compounds to the tissues or cells. To address this challenge, we present here a single siRNA nanocapsule delivery technology, which is achieved by encapsulating a single siRNA molecule within a degradable polymer nanocapsule with a diameter around 20 nm and positive surface charge. As proof-of-concept, since CCR5 is considered a major silencing target of HIV therapy, CCR5-siRNA nanocapsules were delivered into 293T cells and successfully downregulated the CCR5 RNA fused with mCherry reporter RNA. In the absence of human serum, nanocapsules and lipofectamine silenced expression of CCR5-mCherry expression to 8% and 15%, respectively. Such nanocapsules maintain the integrity of siRNA inside even after incubation with ribonuclease and serum for 1 h; under the same conditions, siRNA is degraded in the native form or when formulated with lipofectamine. In the presence of serum, CCR5-siRNA nanocapsules knocked down CCR5-mCherry expression to less than 15% while siRNAs delivered through lipofectamine slightly knocked down the expression to 55%. In summary, this work provides a novel platform for siRNA delivery that can be developed for therapeutic purposes.
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PMID:Single siRNA nanocapsules for enhanced RNAi delivery. 2286 78


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