Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.7.6 (RNA polymerase)
 34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CTLA4Ig, a fusion protein that blocks CD28-B7 costimulation, was studied in a LEW to F344 rat model of chronic cardiac rejection. In rats treated with a single dose of CTLA4Ig (0.5 mg intraperitoneally) 2 d after transplantation, allografts survived significantly longer ( > 70 d in 64%) than in untreated controls or rats treated with control Ig (all rejected within 25 d). Only 25% of grafts from rats treated with a single, high dose of cyclosporine A (25 mg/kg, 2 d after transplantation) survived longer than 70 d. Reverse transcriptase PCR and immunostaining analyses of tissue from 75-d, CTLA4Ig-treated allografts showed reduced expression of the T cell factor IFN-gamma and macrophage activation factors monocyte chemoattractant protein-1, inducible nitric oxide synthase, and galactose/N-acetylgalactosamine macrophage lectin, as well as TGF-beta. Grafts from longterm survivors ( > 120 d) treated with CTLA4Ig showed significant reductions in the frequency and severity of arteriosclerosis in comparison with cyclosporine A-treated rats. Thus, T cell activation is a proximal event in the cascade that culminates in the arteriosclerosis of chronic rejection. Strategies for blocking T cell costimulation may help prevent chronic rejection in clinical transplantation.
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PMID:Chronic cardiac rejection in the LEW to F344 rat model. Blockade of CD28-B7 costimulation by CTLA4Ig modulates T cell and macrophage activation and attenuates arteriosclerosis. 860 41

Functional chemokine receptors and chemokines are expressed by glial cells within the CNS, though relatively little is known about the patterns of neuronal chemokine receptor expression and function. We developed monoclonal antibodies to the CCR1, CCR2, CCR3, CCR6, CXCR2, CXCR3 and CXCR4 chemokine receptors to study their expression in human fetal neurons cultured from brain tissue as well as the clonally derived NT2.N human neuronal cell line (NTera 2/cl.D1). Specific monoclonal antibody labeling demonstrated expression of CCR2, CXCR2, CXCR3 and CXCR4 on neurons from both sources. Co-labeling studies revealed strong expression of CXCR3 and CXCR4 on both dendritic and axonal processes, with a weaker expression of CXCR2 and CCR2. Reverse transcriptase-polymerase chain reaction analysis of pure NT2.N neurons confirmed RNA expression for CCR2, CXCR2, CXCR3 and CXCR4. No changes in the neuronal labeling pattern of chemokine receptor expression were noted when NT2.N neurons were grown on a supporting layer of astrocytes, again consistent with similar patterns seen in primary human fetal brain cultures. Analysis of single-cell calcium transients revealed a robust response to stromal derived factor-1alpha (CXCR4) and melanocyte growth-stimulating activity (CXCR2), and variable response to monocyte chemoattractant protein-1 (CCR2) or interferon-gamma inducible protein-10 (CXCR3). Finally, we detected the release of monocyte chemoattractant protein-1 from pure cultures of NT2.N neurons, but not undifferentiated NT2 cells. These data indicate that individual neurons may not only co-express multiple functional chemokine receptors, but also that neurons themselves produce chemokines which may influence cellular function within the central nervous system.
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PMID:Expression of multiple functional chemokine receptors and monocyte chemoattractant protein-1 in human neurons. 1082 41

The mechanisms underlying the therapeutic efficacy of erythromycin (EM) in diffuse panbronchiolitis (DPB) was investigated. For this purpose, an experimental rabbit model of DPB induced by Pseudomonas aeruginosa inoculation was employed. Daily administration of EM (3 mg x kg x day(-1)) led to an increase in the number of macrophages in bronchoalveolar lavage fluid (BALF) at an early phase, while reducing the size of granulomatous lesions at the late phase without affecting the number of viable bacteria recovered from the infected lung. Reverse transcriptase polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA) and immunohistochemical studies showed that monocyte chemoattractant protein (MCP)-1 was produced in both BALF and infected lung. EM treatment resulted in a significant increase in the level of MCP-1 in BALF, while reducing that of tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-8. EM also increased MCP-1 messenger ribonucleic acid (mRNA) and protein expression in the infected lung. MCP-1 blockade abolished the protective effect of EM, as neutralization of MCP-1 with anti-MCP-1 antibodies reduced the EM-induced increase in the number of macrophages in BALF, and augmented size of the granulomatous lesions, as compared to control. The results of the present study suggest that erythromycin attenuates the pulmonary granuloma formation, at least in part, by increasing the production of monocyte chemoattractant protein-1.
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PMID:Erythromycin attenuates an experimental model of chronic bronchiolitis via augmenting monocyte chemoattractant protein-1. 1140 12

Exposure of human osteoblasts to ultrafine titanium (Ti) particles has been shown to alter osteoblast gene expression. We previously reported that Ti particles can increase IL-6 release and suppress the gene expression of procollagens alpha1[I] and alpha1[III] in human osteoblasts. In this study, we now demonstrate that Ti particles can rapidly induce the chemotactic cytokines interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1), two immediate early stress responsive chemokines important for the activation and chemotaxis of neutrophils and macrophages, respectively. In MG-63 osteosarcoma cells and bone marrow derived primary osteoblasts Ti particles selectively increased the steady state levels of IL-8 and MCP-1 mRNA in a time and concentration dependent manner. The increased chemokine mRNA correlated with increased secretion of IL-8 and MCP-1 protein. Actinomycin D, a potent RNA polymerase II inhibitor, blocked the Ti particle induction of IL-8 and MCP-1 mRNA expression, whereas cycloheximide, which inhibits protein synthesis, failed to inhibit chemokine gene expression suggesting Ti particles directly target activation of chemokine gene transcription. Consistent with a transcriptional mechanism not involving new protein synthesis, we demonstrate that Ti particles induce the binding of the p65 and p50 subunits of the latent transcription factor NF-kappaB to the IL-8 gene promoter. Taken together, these data demonstrate that Ti particles can activate transcription of the stress responsive chemokine genes IL-8 and MCP-1 in human osteoblasts.
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PMID:Titanium particles induce the immediate early stress responsive chemokines IL-8 and MCP-1 in osteoblasts. 1203 22

The repair of an injured bronchial epithelial cell (BEC) monolayer requires proliferation and migration of BECs into the injured area. We hypothesized that BEC monolayer injury results in monocyte chemoattractant protein-1 (MCP-1) production, which initiates the repair process. BECs (BEAS-2B from ATCC) were utilized in this study. MCP-1 interacts with CCR2B receptor (CCR2B), resulting in cell proliferation, haptotaxis, and healing of the monolayer. Reverse transcriptase-polymerase chain reaction (RT-PCR) was employed to verify the presence of CCR2B. CCR2B was not merely present but also inducible by interleukin-2 (IL-2) and lipopolysaccharide (LPS). We demonstrated by immunohistochemistry that BECs express MCP-1 after injury and that receptor expression can be regulated by exposure to IL-2 and LPS. Haptotactic migration of cells was enhanced in the presence of MCP-1 and reduced in the presence of CCR2B antibody. This enhanced or depressed ability of the BECs to perform haptotactic migration was shown to be statistically significant (P < 0.05) when compared to controls. Finally, BECs proliferate in response to MCP-1 as proven by electric cell-substrate impedance sensing (ECIS) technology. MCP-1-specific antibodies were shown to neutralize the MCP-1-mediated BEC proliferation. This cascade of events following injury to the bronchial epithelium may provide insight into the mechanism of the repair process.
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PMID:Induction of MCP-1 expression in airway epithelial cells: role of CCR2 receptor in airway epithelial injury. 1207 56

Macrophages are considered essential for herniated disc resorption, and chemokines may play a role in their recruitment. Here we demonstrate that intervertebral disc cells are capable of producing monocyte chemoattractant protein-1 (MCP-1), a CC chemokine that is chemotactic for macrophages. Nucleus pulposus cells and anulus fibrosus cells were harvested from intervertebral discs of healthy rabbits, and the cells were stimulated with either interleukin (IL)-1beta or tumor necrosis factor (TNF)alpha. Reverse transcriptase polymerase chain reaction demonstrated that IL-1beta and TNFalpha induced mRNA expression for MCP-1 in nucleus pulposus and anulus fibrosus cells. Protein concentrations of MCP-1 in the culture supernatants were quantitated by fluoroimmunoassay, which showed that nucleus pulposus and anulus fibrosus cells dose- and time-dependently produced MCP-1 after IL-1beta- and TNFalpha-stimulation, an event that was completely abrogated by IL-1 receptor antagonist and anti-TNFalpha monoclonal antibody, respectively. Nucleus pulposus cells produced significantly higher levels of MCP-1 than did anulus fibrosus cells. Immunohistochemically, the intensity of MCP-1 positive cells in nucleus pulposus cells was stronger than that in anulus fibrosus cells. Altogether, our data clearly demonstrated the production of MCP-1 in intervertebral disc cells, suggesting the possible involvement of disc cells in an early stage of macrophage infiltration.
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PMID:Expression of monocyte chemoattractant protein-1 in primary cultures of rabbit intervertebral disc cells. 1247 43

Intraalveolar activation of the coagulation system due to reduced fibrinolytic function plays a critical role in the pathogenesis of interstitial lung disease. Recently, a new potent inhibitor of fibrinolysis, thrombin-activatable fibrinolysis inhibitor, has been isolated and characterized from human plasma. This study evaluated the levels of thrombin-activatable fibrinolysis inhibitor and protein C inhibitor, another suppressor of fibrinolysis, in the bronchoalveolar lavage fluid from patients with interstitial lung disease. There were 82 patients with interstitial lung disease and 8 normal subjects. The bronchoalveolar lavage fluid levels of thrombin-activatable fibrinolysis inhibitor and protein C inhibitor were significantly higher in all patients with interstitial lung disease than in normal subjects. Both inhibitors of fibrinolysis were significantly and inversely correlated with fibrinolytic activity in all patients. The levels of thrombin-activatable fibrinolysis inhibitor were significantly correlated with those of protein C inhibitor, thrombin-antithrombin complex, and monocyte chemoattractant protein-1. Reverse transcriptase-polymerase chain reaction showed that alveolar macrophages isolated from patients with interstitial lung disease as well as immortalized lung epithelial cell lines express thrombin-activatable fibrinolysis inhibitor antigen. Overall, these findings suggest that thrombin-activatable fibrinolysis inhibitor and protein C inhibitor may play important roles in the mechanism of intraalveolar hypofibrinolysis associated with interstitial lung diseases.
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PMID:Thrombin-activatable fibrinolysis inhibitor and protein C inhibitor in interstitial lung disease. 1279 52

Systemic sclerosis is a connective tissue disease characterized by excessive deposition of extracellular matrix in the skin as well as various internal organs. Cellular infiltrates are found in the dermis in early systemic sclerosis, which are suggested to play an important part. Recent studies suggest the involvement of monocyte chemoattractant protein-1, a C-C chemokine, in the fibrotic process. This study examines the role of monocyte chemoattractant protein-1 in the induction of dermal sclerosis in a murine model of bleomycin-induced scleroderma. Immunohistochemical analysis showed that expression of monocyte chemoattractant protein-1 in the infiltrating mononuclear cells was enhanced at 2 to 3 wk following bleomycin treatment, whereas expression of monocyte chemoattractant protein-1 in fibroblasts was detected at later stages in the sclerotic skin. Reverse transcriptase-polymerase chain reaction analysis showed that monocyte chemoattractant protein-1 mRNA expression in the lesional skin peaked at 2 to 3 wk following bleomycin treatment. Expression of CCR-2, a major receptor for monocyte chemo-attractant protein-1, was also upregulated in the lesional skin at both protein and mRNA levels following bleomycin treatment. Administration of anti-monocyte chemoattractant protein-1 neutralizing antibody together with local bleomycin treatment reduced dermal sclerosis, along with a decrease of collagen content in the skin as well as mRNA expression of type I collagen. In vitro analysis showed that stimulation with monocyte chemoattractant protein-1 (10 ng per mL) upregulated alpha1(I) collagen and decorin mRNA expression in normal dermal fibroblasts, whereas mRNA levels of fibronectin and biglycan were not altered. These data suggest that monocyte chemoattractant protein-1 and CCR-2 signaling plays an important part in the pathogenesis of bleomycin-induced scleroderma. Monocyte chemoattractant protein-1 may contribute to the induction of dermal sclerosis via its direct effect of upregulation of mRNA expression of extracellular matrix on fibroblasts, as well as indirect effect mediated by a number of cytokines released from immunocytes recruited into the lesional skin.
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PMID:Role of monocyte chemoattractant protein-1 and its receptor,CCR-2, in the pathogenesis of bleomycin-induced scleroderma. 1292 9

The purpose of this study is to investigate the sequential expression of certain chemokines and chemokine receptors in the iris-ciliary body and popliteal lymph nodes of Lewis rats and, thus, to establish their roles in experimental autoimmune anterior uveitis. Uveitis was induced with the injection of melanin-associated antigen intraperitoneally and into the left foot. The clinical severity of the uveitis was scored. At defined time points, CC chemokines (monocyte chemoattractant protein-1, macrophage inflammatory protein-1, and regulated-upon-activation normal T-cell expressed and secreted), CXC chemokines (interferon gamma-inducible protein-10, stromal-derived factor-1, and interleukin-8), and receptor (CCR2, CCR3, CCR5, CXCR1, CXCR2, CXCR3, and CXCR4) mRNA expression were semiquantified by using a reverse-transcriptase reaction followed by polymerase chain reaction. The concentrations of macrophage inflammatory protein-1 and regulated-upon-activation normal T-cell expressed and secreted in aqueous humor were determined by means of enzyme-linked immunosorbent assay. Levels of monocyte chemoattractant protein-1, macrophage inflammatory protein-1 and interferon gamma-inducible protein-10 started increasing before the clinical onset of disease; these might have been involved in the initial recruitment of inflammatory cells. The level of regulated-upon-activation normal T-cell mRNA, however, started rising concurrently with the onset of clinical disease, suggesting that this chemokine may exert amplifying role in generating uveitis. Stromal-derived factor-1 exhibited an early and high level of expression with the increase of cognate receptor, CXCR4, indicating that stromal-derived factor-1 plays a role in either promoting angiogenesis or attracting for T-cells. Instead of upregulation like other chemokine receptors, interleukin-8 receptors, CXCR1and CXCR2, mRNA could not be detected in accord with the increase of interleukin-8. These findings appeared that downregulation of chemokine receptors on neutrophils may make themselves less respond to interleukin-8 and subsequently lead to decreased recruitment of neutrophils into the iris-ciliary body. In addition, the expression of chemokine receptors in popliteal lymph nodes were earlier than those in the iris-ciliary body. This sequence of expression may reflect the process of T lymphocytes maturation and differentiation. Monocyte chemoattractant protein-1 protein was immunohistologically detected in the ciliary epithelium and infiltrating leukocytes. The above results suggest that chemokines, which act on T cells and monocytes, are sequentially upregulated during the clinical course of experimental autoimmune anterior uveitis, and thus, may contribute to the pathogenesis of acute anterior uveitis.
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PMID:Expression of chemokine and receptors in Lewis rats with experimental autoimmune anterior uveitis. 1510 11

Legionella pneumophila causes community-acquired pneumonia with high mortality, but little is known about its interaction with the alveolar epithelium. The aim of this study was to investigate whether L. pneumophila infection of lung epithelial cells (A549) resulted in pro-inflammatory activation. L. pneumophila infection induced liberation of interleukin (IL)-2, -4, -6, -8 and -17, monocyte chemoattractant protein-1, tumour necrosis factor-alpha, IL-1beta, interferon-gamma and granulocyte colony-stimulating factor, but not of IL-5, -7, -10, -12 (p70) or -13 or granulocyte-macrophage colony-stimulating factor. The present study focused on IL-8 and found induction by L. pneumophila strains 130b, Philadelphia 1, Corby and, to a lesser extent, JR32. Knockout of dotA, a central gene involved in type IVB secretion, did not alter IL-8 induction, whereas lack of flagellin significantly reduced IL-8 release by Legionella. Moreover, p38 mitogen-activated protein kinase (MAPK) was activated and kinase inhibition reduced secretion of induced cytokines, with the exception of IL-2 and granulocyte colony-stimulating factor. In contrast, inhibition of the MAPK kinase 1/extracellular signal-regulated kinase pathway only reduced the expression of a few cytokines. L. pneumophila also induced binding of nuclear factor-kappaB subunit RelA/p65 and RNA polymerase II to the il8 promoter, and a specific inhibitor of the inhibitor of nuclear factor-kappaB complex dose-dependently lowered IL-8 expression. Taken together, Legionella pneumophila activated p38 mitogen-activated protein kinase- and nuclear factor-kappaB/RelA pathway-dependent expression of a complex pattern of cytokines by human alveolar epithelial cells, presumably contributing to the immune response in legionellosis.
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PMID:Legionella pneumophila-induced NF-kappaB- and MAPK-dependent cytokine release by lung epithelial cells. 1697 6


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