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:3.1.27.5 (RNase)
17,967 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In an attempt to understand potential novel functions of receptors in vivo, we evaluated gene expression after cross-linking the activating Ly-49D mouse NK receptor. Gene expression was evaluated using a mouse GEM 2 microarray chip (Incyte Genomics, St. Louis, MO). Each chip displays a total of 8734 elements. The strongly induced genes fell into two categories: 1) soluble factors and 2) apoptotic genes. The majority of the strongly induced mRNAs as analyzed by microarray hybridization were chemokine genes. RNase protection assays and chemokine protein production analysis validated the microarray results, as cross-linking the Ly-49D mouse NK receptor induced high levels of IFN-gamma, lymphotactin, macrophage-inflammatory protein (MIP)1alpha, and MIP1beta. This gene expression was specific because other chemokines were not induced by anti-Ly-49D receptors. In addition, a series of pharmacological inhibitors were used to identify the key signaling pathways involved in the cellular response. The primary Ly-49D signaling for IFN-gamma production is predominantly mediated through Src kinase pathways involving membrane proximal events, whereas MIP1alpha and MIP1beta gene induction is more complex and may involve multiple biochemical pathways. Thus, we conclude that a primary role for the activating NK receptors in vivo may be to trigger soluble factor production and regulation of the immune response. This would place NK cells and their activating Ly-49 receptors as important initiators of microbial immunity and key elements of the innate immune system.
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PMID:Activating Ly-49 NK receptors: central role in cytokine and chemokine production. 1129 Jul 79

We studied the expression of cytokines, chemokines, and chemokine receptors by the RNase protection assay in chlamydia-pulsed dendritic cells to better understand their potent anti-chlamydial immunizing properties. We found that chlamydia-pulsed dendritic cells express a complex profile of inflammatory and immunomodulatory molecules. These include CCR-7, interleukin-12, and interferon-induced protein 10, molecules that might influence the homing of pulsed dendritic cells to the site of chlamydial infection and the induction of a local protective CD4(+) Th1 cellular immunity.
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PMID:Expression of genes encoding Th1 cell-activating cytokines and lymphoid homing chemokines by chlamydia-pulsed dendritic cells correlates with protective immunizing efficacy. 1140 13

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

Extravascular fibrin deposition is an early and persistent hallmark of inflammatory responses. Fibrin is generated from plasma-derived fibrinogen, which escapes the vasculature in response to endothelial cell retraction at sites of inflammation. Our ongoing efforts to define the physiologic functions of extravasated fibrin(ogen) have led to the discovery, reported here, that fibrinogen stimulates macrophage chemokine secretion. Differential mRNA expression analysis and RNase protection assays revealed that macrophage inflammatory protein-1alpha (MIP-1alpha), MIP-1beta, MIP-2, and monocyte chemoattractant protein-1 are fibrinogen inducible in the RAW264.7 mouse macrophage-like cell line, and ELISA confirmed that both RAW264.7 cells and primary murine thioglycolate-elicited peritoneal macrophages up-regulate the secretion of monocyte chemoattractant protein-1 >100-fold upon exposure to fibrinogen. Human U937 and THP-1 precursor-1 (THP-1) monocytic cell lines also secreted chemokines in response to fibrinogen, upon activation with IFN-gamma and differentiation with vitamin D(3), respectively. LPS contamination could not account for our observations, as fibrinogen-induced chemokine secretion was sensitive to heat denaturation and was unaffected by the pharmacologic LPS antagonist polymyxin B. Nevertheless, fibrinogen- and LPS-induced chemokine secretion both apparently required expression of functional Toll-like receptor 4, as each was diminished in macrophages derived from C3H/HeJ mice. Thus, innate responses to fibrinogen and bacterial endotoxin may converge at the evolutionarily conserved Toll-like recognition molecules. Our data suggest that extravascular fibrin(ogen) induces macrophage chemokine expression, thereby promoting immune surveillance at sites of inflammation.
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PMID:Fibrinogen stimulates macrophage chemokine secretion through toll-like receptor 4. 1150 36

Chemokines are small chemotactic cytokines that modulate leukocyte recruitment and activation during inflammation. Here, we describe the role of macrophage inflammatory protein-1alpha (MIP-1alpha) during cuprizone intoxication, a model where demyelination of the CNS features a large accumulation of microglia/macrophage without T cell involvement or blood-brain barrier disruption. RNase protection assays showed that mRNA for numerous chemokines were up-regulated during cuprizone treatment in wild-type, C57BL/6 mice. RANTES, inflammatory protein-10, and monocyte chemoattractant protein-1 showed greatest expression with initiation of insult at 1-2 wk of treatment, whereas MIP-1alpha and beta increased later at 4-5 wk, coincident with peak demyelination and cellular accumulation. The function of MIP-1alpha during demyelination was tested in vivo by exposing MIP-1alpha knockout mice (MIP-1alpha(-/-)) to cuprizone and comparing pathology to wild-type mice. Demyelination at 3.5 wk of treatment was significantly decreased in MIP-1alpha(-/-) mice ( approximately 36% reduction), a result confirmed by morphology at the electron microscopic level. The delay in demyelination was correlated to apparent decreases in microglia/macrophage and astrocyte accumulation and in TNF-alpha protein levels. It was possible that larger effects of the MIP-1alpha deficiency were being masked by other redundant chemokines. Indeed, RNase protection assays revealed increased expression of several chemokine transcripts in both untreated and cuprizone-treated MIP-1alpha(-/-) mice. Nonetheless, despite this possible compensation, our studies show the importance of MIP-1alpha in demyelination in the CNS and highlight its effect, particularly on cellular recruitment and cytokine regulation.
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PMID:Absence of macrophage-inflammatory protein-1alpha delays central nervous system demyelination in the presence of an intact blood-brain barrier. 1150 46

Human peritoneal mesothelial cells (HMC) play an important role in inflammatory processes by their ability to produce various cytokines and chemokines, such as monocyte chemoattractant protein 1 (MCP-1) and interleukin 8 (IL-8). In this study we investigated the effect of experimentally generated hyaluronan (HA) fragments, degradation products of the extracellular matrix component hyaluronan, which accumulate at inflammatory sites, on the expression of MCP-1 and IL-8 in cultured HMC. MCP-1 and IL-8 mRNA expression was determined by RNase protection assays, and protein levels in the supernatants were measured by enzyme-linked immunosorbent assays. HA fragments with a molecular mass of approximately 1-7x10(5) daltons upregulate MCP-1 and IL-8 synthesis in HMC dose and time dependently. The effect of HA fragments could be blocked by Ro31-8220, a specific protein kinase C inhibitor, and by PD98059, an inhibitor of the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway. Upregulation of chemokine synthesis was preceded by an increase in NF-kappaB and AP-1 DNA-binding activity, suggesting that these transcription factors are activated to increase MCP-1 and IL-8 expression by HA fragments. These data demonstrate that HA fragments markedly enhance the mRNA expression and protein synthesis of MCP-1 and IL-8 in HMC. In concert with previous findings, our observations indicate that enhanced levels of HA, which are present in the peritoneal cavity of peritoneal dialysis patients, may account for a locally increased chemokine production.
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PMID:Hyaluronan fragments induce the synthesis of MCP-1 and IL-8 in cultured human peritoneal mesothelial cells. 1151 74

The Paramyxovirus respiratory syncytial virus (RSV) is the primary etiologic agent of serious epidemic lower respiratory tract disease in infants, immunosuppressed patients, and the elderly. Lower tract infection with RSV is characterized by a pronounced peribronchial mononuclear infiltrate, with eosinophilic and basophilic degranulation. Because RSV replication is restricted to airway epithelial cells, where RSV replication induces potent expression of chemokines, the epithelium is postulated to be a primary initiator of pulmonary inflammation in RSV infection. The spectrum of RSV-induced chemokines expressed by alveolar epithelial cells has not been fully investigated. In this report, we profile the kinetics and patterns of chemokine expression in RSV-infected lower airway epithelial cells (A549 and SAE). In A549 cells, membrane-based cDNA macroarrays and high-density oligonucleotide probe-based microarrays identified inducible expression of CC (I-309, Exodus-1, TARC, RANTES, MCP-1, MDC, and MIP-1 alpha and -1 beta), CXC (GRO-alpha, -beta, and -gamma, ENA-78, interleukin-8 [IL-8], and I-TAC), and CX(3)C (Fractalkine) chemokines. Chemokines not previously known to be expressed by RSV-infected cells were independently confirmed by multiprobe RNase protection assay, Northern blotting, and reverse transcription-PCR. High-density microarrays performed on SAE cells confirmed a similar pattern of RSV-inducible expression of CC chemokines (Exodus-1, RANTES, and MIP-1 alpha and -1 beta), CXC chemokines (I-TAC, GRO-alpha, -beta, and -gamma, and IL-8), and Fractalkine. In contrast, TARC, MCP-1, and MDC were not induced, suggesting the existence of distinct genetic responses for different types of airway-derived epithelial cells. Hierarchical clustering by agglomerative nesting and principal-component analyses were performed on A549-expressed chemokines; these analyses indicated that RSV-inducible chemokines are ordered into three related expression groups. These data profile the temporal changes in expression by RSV-infected lower airway epithelial cells of chemokines, chemotactic proteins which may be responsible for the complex cellular infiltrate in virus-induced respiratory inflammation.
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PMID:Expression of respiratory syncytial virus-induced chemokine gene networks in lower airway epithelial cells revealed by cDNA microarrays. 1153 68

Expression of transforming growth factor alpha (TGFalpha), a member of the epidermal growth factor (EGF) family, is a general response of adult murine motoneurons to genetic and experimental lesions, TGFalpha appearing as an inducer of astrogliosis in these situations. Here we address the possibility that TGFalpha expression is not specific to pathological situations but may participate to the embryonic development of motoneurons. mRNA of TGFalpha and its receptor, the EGF receptor (EGFR), were detected by ribonuclease protection assay in the ventral part of the cervical spinal cord from embryonic day 12 (E12) until adult ages. Reverse transcription-PCR amplification of their transcripts from immunopurified E15 motoneurons, associated with in situ double-immunohistological assays, identified embryonic motoneurons as cellular sources of the TGFalpha-EGFR couple. In vitro, TGFalpha promoted the survival of immunopurified E15 motoneurons in a dose-dependent manner, with a magnitude similar to BDNF neuroprotective effects at equivalent concentrations. In a transgenic mouse expressing a human TGFalpha transgene under the control of the metallothionein 1 promoter, axotomy of the facial nerve provoked significantly less degeneration in the relevant motor pool of 1-week-old mice than in wild-type animals. No protection was observed in neonates, when the transgene exhibits only weak expression levels in the brainstem. In conclusion, our results point to TGFalpha as a physiologically relevant candidate for a neurotrophic role on developing motoneurons. Its expression by the embryonic motoneurons, which also synthesize its receptor, suggests that this chemokine is endowed with the capability to promote motoneuron survival in an autocrine-paracrine manner.
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PMID:Transforming growth factor alpha: a promoter of motoneuron survival of potential biological relevance. 1154 18

Previous studies have documented that the ability to heal wounds declines with age. Although many factors contribute to this age-associated deficit, one variable that has not been carefully examined is leukocyte recruitment and function in wounds. This investigation compares the inflammatory response in excisional wounds of young (age 8 wk) and aged (age 22 mo) mice. In the early inflammatory response, neutrophil content of wounds was similar for both aged and young mice. In contrast, macrophage levels were 56% higher in aged versus young mice (81 +/- 20 vs 52 +/- 13 cells per mm2). In the later inflammatory response, wounds of aged mice exhibited a delay in T cell infiltration, with maximum T cell levels at day 10 in aged mice versus day 7 in young mice. Despite this delay, the eventual peak concentration of T cells was 23% higher in the wounds of aged mice (152 +/- 11 cells per mm2 vs 124 +/- 21cells per mm2). The observed alterations in inflammatory cell content suggested that chemokine production might be altered with age. An elevation of monocyte chemoattractant protein (MCP-1) levels was observed in wounds of aged mice. RNase protection studies, however, revealed that the production of most chemokines, including MIP-2, MIP-1alpha, MIP-1beta, and eotaxin, tended to decline with age. Because optimal wound healing requires both appropriate macrophage infiltration and phagocytic activity, phagocytosis was examined. Compared to young mice, wound macrophages from aged mice exhibited a 37%-43% reduction in phagocytic capacity. Taken together, the data demonstrate age-related shifts in both macrophage and T cell infiltration into wounds, alterations in chemokine content, and a concurrent decline in wound macrophage phagocytic function. These alterations may contribute to the delayed repair response of aging.
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PMID:Age-related alterations in the inflammatory response to dermal injury. 1171 Sep 9

During human pregnancy, the uterus is infiltrated by a population of maternal leukocytes that co-exist with fetal cytotrophoblasts occupying the decidua and uterine blood vessels. These immune cells, termed "decidual granulated leukocytes," are composed predominantly (70%) of the CD56(bright) subset of natural killer cells, accompanied by T cells (15%) and macrophages (15%). The mechanisms underlying the recruitment of these cells are unknown, but by analogy to other systems, chemokines are likely to be involved. We examined the expression patterns of 14 chemokines in the decidualized uterine wall by in situ hybridization, and the expression of chemokine receptors on decidual leukocytes by RNase protection. The striking concordance between the expression of chemokines in the uterus and their receptors on decidual leukocytes allowed us to identify numerous receptor-ligand pairs that may recruit the latter cells to the uterus during pregnancy. Additionally, chemokine expression patterns suggested other, nonimmune functions for these molecules, including a role in cytotrophoblast differentiation. Together, our results imply that chemokine networks serve important functions at the maternal-fetal interface.
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PMID:Chemokine ligand and receptor expression in the pregnant uterus: reciprocal patterns in complementary cell subsets suggest functional roles. 1173 70


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