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)

Activation of T cells in the intestinal mucosa in response to gluten exposure is thought to play a key role in the pathogenesis of coeliac disease. Moreover, the response of the rectal mucosa to gluten challenge has been considered a useful predictor of gluten sensitivity in coeliac disease. In the present study, we assessed early changes in the expression of proinflammatory cytokine genes and the T cell receptor (TCR) Vbeta repertoire in the rectal mucosa of coeliac disease patients following experimental gluten challenge. Cytokine gene expression was assessed in rectal mucosal biopsies from coeliac disease subjects and controls before and after rectal gluten challenge using quantitative reverse transcription polymerase chain reaction analysis, and the TCR Vbeta repertoire was characterized using a multiprobe RNase protection assay. Marked up-regulation of expression of the C-X-C chemokine IL-8, the proinflammatory cytokine IL-1beta, and the C-C chemokine monocyte chemotactic protein-1 occurred within 24 h of rectal gluten challenge in coeliac disease subjects, but not in controls. Furthermore, these changes occurred in the absence of parallel changes in the expressed repertoire of TCR Vbeta genes in the rectal mucosa. Thus, an increased expression of proinflammatory cytokine genes precedes the expansion of antigen-specific T cell populations in the early period following experimental exposure of the rectal mucosa of coeliac disease patients to gluten. These findings provide new insights into pathways that may be involved in the activation or reactivation of coeliac disease.
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PMID:Increased proinflammatory cytokine gene expression in the colonic mucosa of coeliac disease patients in the early period after gluten challenge. 901 Feb 69

NK cells migrate in response to C-C chemokines, including monocyte chemotactic protein-1 (MCP-1) and MCP-3. Increased migration was observed in IL-2-activated NK cells. It was therefore of interest to define the expression in resting and activated NK cells of the MCP-1 receptor (CCR2) for which two cDNAs (A and B) have been described. Specific oligonucleotides and reverse-transcriptase PCR revealed the presence in activated NK cells and mononuclear phagocytes of the fragments expected on the basis of the reported cDNAs. In addition, amplification with a common A/B- and an A-specific oligonucleotide yielded an unexpected, abundant, 1649-bp fragment. Sequence analysis as well as Northern blotting and RNase protection with different probes revealed that the CCR2 gene is expressed in activated NK cells and mononuclear phagocytes as a predominant long transcript (3.4 kb) consisting of CCR2B, followed by a novel sequence (X), corresponding to an intron in the genome, and by a CCR2A-specific portion. The predominant long transcript is polyadenylated and present in the cytoplasm. The augmented migratory capacity of IL-2 activated vs resting NK cells was associated with increased CCR2 transcript levels.
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PMID:IL-2-regulated expression of the monocyte chemotactic protein-1 receptor (CCR2) in human NK cells: characterization of a predominant 3.4-kilobase transcript containing CCR2B and CCR2A sequences. 905 2

Fibrosis, characterized by the accumulation of collagen, is a consequence of a chronic inflammatory response. The purpose of this study was to determine if the mRNA expression of the chemokines, lymphotactin (Ltn), RANTES, eotaxin, macrophage inflammatory protein (MIP)-1 alpha, -1 beta, and -2, interferon-inducible protein 10 (IP-10), and monocyte chemotactic protein-1 (MCP-1), are altered during the development of radiation-induced pneumonitis and fibrosis. Further, we wished to determine if these changes differ between two strains of mice that vary in their sensitivity to radiation fibrosis. Fibrosis-sensitive (C57BL/6) and fibrosis-resistant (C3H/HeJ) mice were irradiated with a single dose of 12.5 Gy to the thorax. Total lung RNA was prepared and hybridized utilizing RNase protection assays. Data were quantified by phosphorimaging and results normalized to a constituitively expressed mRNA L32. 8 weeks post-irradiation most chemokines measured were elevated to varying degrees. The degree of elevation of each chemokine was identical in both strains. This suggested that chemotactic activity for neutrophils, macrophages, and lymphocytes were occurring during pneumonitis. By 26 weeks post-irradiation, messages encoding Ltn, RANTES, IP-10, and MCP-1 were elevated only in fibrosis sensitive (C57BL/6) mice. In situ hybridization demonstrated that MCP-1 and RANTES transcripts were produced predominantly from macrophages and lymphocytes. These studies suggest that lymphocytic recruitment and activation are key components of radiation-induced fibrosis.
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PMID:Alterations in the expression of chemokine mRNA levels in fibrosis-resistant and -sensitive mice after thoracic irradiation. 963 54

Recent evidence has suggested that epithelial cells may contribute to the inflammatory response in the lung after exposure to crystalline silica through the production of and response to specific growth factors, chemokines, and cytokines. However, the exact cellular and molecular responses of epithelial cells to silica exposure remains unclear. Using a murine alveolar type II cell line [murine lung epithelial (MLE)-15 cell line], we measured the early changes in various cytokine and chemokine mRNA species after exposure of the cells to 4-35 microgram/cm2 of silica (cristobalite), interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, and lipopolysaccharide (LPS) alone or in combination. Total mRNA was isolated and assayed with an RNase protection assay after 6 and 24 h of exposure. Cristobalite exposure alone led to an increase in monocyte chemotactic protein (MCP)-1, macrophage inflammatory protein (MIP)-2, and regulated on activation normal T cells expressed and secreted (RANTES) mRNAs. Treatment with IFN-gamma alone increased MCP-1 mRNA levels. Treatment with TNF-alpha or LPS alone led to an increase in MCP-1 and MIP-2 mRNA. The combination of cristobalite plus TNF-alpha led to an additive increase in MCP-1 and MIP-2, whereas cristobalite plus IFN-gamma or LPS had a synergistic effect. We also found with a TNF-alpha-neutralizing antibody that TNF-alpha plays a major role in mediating the type II cell chemokine response to cristobalite exposure. The results indicate that the cristobalite-induced chemokine response in the lung epithelium is mediated in part by TNF-alpha and can be enhanced by macrophage- and lymphocyte-derived inflammatory mediators in an additive and synergistic fashion.
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PMID:Silica-induced chemokine expression in alveolar type II cells is mediated by TNF-alpha. 984 48

We have shown previously that epithelial cells may contribute to the inflammatory response in the lung after exposure to crystalline silica through the production of and response to specific chemokines and cytokines. However, the exact cellular and molecular responses of epithelial cells to silica exposure remain unclear. We hypothesize that non-oxidant-mediated silica-cell interactions lead to the upregulation of tumor necrosis factor-alpha (TNF-alpha), whereby TNF-alpha-induced generation of reactive oxygen species (ROS) leads to the activation of the monocyte chemotactic protein (MCP)-1 and macrophage inflammatory protein (MIP)-2 genes. Using a murine alveolar type II cell line, murine lung epithelial (MLE)-15, we measured the early changes in TNF-alpha, MCP-1, and MIP-2 mRNA species after exposure of the cells to 18 micrograms/cm2 silica (cristobalite) in combination with various antioxidants. Total mRNA was isolated and assayed using an RNase protection assay after 6 h of particle exposure. We found that extracellular GSH could completely attenuate the cristobalite-induced expression of MCP-1 and MIP-2 mRNAs, whereas TNF-alpha mRNA levels were unaltered. We also found using the oxidant-sensitive dye 6-carboxy-2', 7'-dichlorodihydrofluorescein diacetate di(acetoxymethyl ester) that treatment of MLE-15 cells with cristobalite and TNF-alpha (1 ng/ml) resulted in ROS production. This ROS production could be inhibited with extracellular GSH treatment, and in the case of cristobalite-induced ROS, inhibition was also achieved with an anti-TNF-alpha antibody. The results support the hypothesis that TNF-alpha mediates cristobalite-induced MCP-1 and MIP-2 expression through the generation of ROS.
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PMID:Silica-induced chemokine expression in alveolar type II cells is mediated by TNF-alpha-induced oxidant stress. 1036 23

Endothelial cell proliferation and migration may play a central role in angiogenesis, wound healing, and atherosclerosis. Although CXC chemokines can act on endothelial cells by influencing proliferation, an involvement of CC chemokines and endothelial expression of chemokine receptors remains to be elucidated. Reverse transcription-polymerase chain reaction, RNase protection, Western blot, and flow cytometric analysis showed that human umbilical vein endothelial cells express mRNA and surface protein of the monocyte chemotactic protein-1 (MCP-1) receptor CCR2, which was upregulated by inflammatory cytokines. MCP-1 induced migration of endothelial cells in a transwell assay, which was inhibited by the 9-76 MCP-1 receptor antagonist. Increased secretion of MCP-1 or interleukin-8, but not RANTES, on endothelial injury suggested a functional role of CCR2 in wound repair as measured by ELISA. After mechanical injury to endothelial monolayers, which spontaneously closed within 24 hours, wound repair was delayed by the 9-76 antagonist and by a blocking monoclonal antibody to MCP-1, but not to interleukin-8, and was improved by exogenous MCP-1. This was confirmed by quantification of cell migration into the wound area, whereas proliferation and viability were unaltered by MCP-1 or its analogue. Notably, immunohistochemistry of inflamed tissue revealed CCR2 staining on arterial, venous, and venular endothelium affected by cellular infiltration. This is the first demonstration of endothelial CCR2 expression ex vivo, inferring its involvement in inflammatory conditions. Thus endothelial cells express functional CCR2 that may have important implications for endothelial wound repair and inflammatory reactions.
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PMID:Expression of CCR2 by endothelial cells : implications for MCP-1 mediated wound injury repair and In vivo inflammatory activation of endothelium. 1047 49

Endothelial synthesis of the C-C chemokine monocyte chemotactic protein-1 (MCP-1) has been implicated in the regulation of monocyte recruitment for extravascular pools under both physiologic and inflammatory conditions. We designed and characterized five antisense phosphorothioate oligodeoxynucleotides (PS-ODN) targeting MCP-1 secretion by human pulmonary artery endothelial cells (HPAEC) and pulmonary microvascular endothelial cells (HMVEC-L). The most effective PS-ODN (MCP-1 AS 2) dose-dependently suppressed the secretion of MCP-1 but not the secretion of the C-X-C chemokine interleukin-8 (IL-8) in both HPAEC and HMVEC-L in the nanomolar concentration range. Mismatch controls bearing 2 or 4 bp substitutions showed markedly reduced inhibitory capacity. MCP-1 mRNA levels were not affected even at the highest PS-ODN doses employed (ribonuclease protection assay), suggesting a translational arrest of MCP-1 production. Accordingly, PS-ODN exhibited no nonspecific side effects on immediate-early gene regulation of the transcription factor nuclear factor-kappaB (NF-kappaB), as analyzed by gel shift assays. Antisense pretreatment of HPAEC reduced the monocyte chemotactic bioactivity liberated from tumor necrosis factor-alpha (TNF-alpha)-activated endothelial cells (EC) and reduced the TNF-alpha-induced transendothelial monocyte migration. We conclude that nanomolar concentrations of specific antisense oligodeoxynucleotides effectively inhibit human endothelial MCP-1 synthesis and may thus provide a rational approach to modulate monocyte recruitment under inflammatory conditions.
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PMID:Antisense oligomers for selective suppression of MCP-1 synthesis in human pulmonary endothelial cells. 1090 55

The present study examined the roles of peroxisome proliferator-activated receptors (PPAR) in activation of hepatic stellate cells (HSC), a pivotal event in liver fibrogenesis. RNase protection assay detected mRNA for PPARgamma1 but not that for the adipocyte-specific gamma2 isoform in HSC isolated from sham-operated rats, whereas the transcripts for neither isoforms were detectable in HSC from cholestatic liver fibrosis induced by bile duct ligation (BDL). Semi-quantitative reverse transcriptase-polymerase chain reaction confirmed a 70% reduction in PPARgamma mRNA level in HSC from BDL. Nuclear extracts from BDL cells showed an expected diminution of binding to PPAR-responsive element, whereas NF-kappaB and AP-1 binding were increased. Treatment of cultured-activated HSC with ligands for PPARgamma (10 microm 15-deoxy-Delta(12,14)-PGJ(2) (15dPGJ(2)); 0.1 approximately 10 microm BRL49653) inhibited DNA and collagen synthesis without affecting the cell viability. Suppression of HSC collagen by 15dPGJ(2) was abrogated 70% by the concomitant treatment with a PPARgamma antagonist (GW9662). HSC DNA and collagen synthesis were inhibited by WY14643 at the concentrations known to activate both PPARalpha and gamma (>100 microm) but not at those that only activate PPARalpha (<10 microm) or by a synthetic PPARalpha-selective agonist (GW9578). 15dPGJ(2) reduced alpha1(I) procollagen, smooth muscle alpha-actin, and monocyte chemotactic protein-1 mRNA levels while inducing matrix metalloproteinase-3 and CD36. 15dPGJ(2) and BRL49653 inhibited alpha1(I) procollagen promoter activity. Tumor necrosis factor alpha (10 ng/ml) reduced PPARgamma mRNA, and this effect was prevented by the treatment with 15dPGJ(2). These results demonstrate that HSC activation is associated with the reductions in PPARgamma expression and PPAR-responsive element binding in vivo and is reversed by the treatment with PPARgamma ligands in vitro. These findings implicate diminished PPARgamma signaling in molecular mechanisms underlying activation of HSC in liver fibrogenesis and the potential therapeutic value of PPARgamma ligands for liver fibrosis.
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PMID:Peroxisome proliferator-activated receptors and hepatic stellate cell activation. 1096 82

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

To evaluate the role of CCR2 in allergic asthma, mutant mice deficient in CCR2 (CCR2(-/-)) and intact mice were sensitized with i.p. OVA with alum on days 0 and 7, and challenged by inhalation with nebulization of either OVA or saline. Airway hyperreactivity, measured by the methacholine-provoked increase in enhanced pause, was significantly increased (p < 0.05) in OVA-challenged CCR2(-/-) mutant mice, compared with comparably challenged CCR2(+/+) mice. OVA-challenged CCR2(-/-) mutants also were also found to have enhanced bronchoalveolar lavage fluid eosinophilia, peribronchiolar cellular cuffing, and Ig subclass switching, with increase in OVA-specific IgG(1) and IgE. In addition, RNase protection assay revealed increased whole lung expression of IL-13 in OVA-challenged CCR2(-/-) mutants. Unexpectedly, serum monocyte chemotactic protein-1 levels were 8-fold higher in CCR2(-/-) mutants than in CCR2(+/+) mice sensitized to OVA, but OVA challenge had no additional effect on circulating monocyte chemotactic protein-1 in either genotype. Ag stimulation of lymphocytes isolated from OVA-sensitized CCR2 mutants revealed a significant increase (p < 0.05) in IL-5 production, which differed from OVA-stimulated lymphocytes from sensitized CCR2(+/+) mice. These experiments demonstrate an enhanced response in airway reactivity and in lung inflammation in CCR2(-/-) mutant mice compared with comparably sensitized and challenged CCR2(+/+) mice. These observations suggest that CC chemokines and their receptors are involved in immunomodulation of atopic asthma.
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PMID:Enhanced airway Th2 response after allergen challenge in mice deficient in CC chemokine receptor-2 (CCR2). 1129 Aug 2


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