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:2.7.7.6 (RNA polymerase)
34,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies suggest that interleukin-6 (IL-6) is produced in the intestinal mucosa during sepsis and endotoxemia and that the enterocyte may be a source of IL-6 in these conditions. The regulation of IL-6 production in the enterocyte is not fully understood. We tested the hypothesis that IL-6 production in the enterocyte is regulated by proinflammatory cytokines. This was done by treating cultured Caco-2 cells, a transformed human intestinal epithelial cell line, with different concentrations of tumor necrosis factor-alpha (TNF-alpha), IL-1 beta, IL-6 or interferon-gamma (IFN-gamma). IL-6 production by the Caco-2 cells was determined by ELISA. The expression of IL-6 mRNA was determined by reverse-transcriptase polymerase chain reaction. IL-6 was not produced in unstimulated Caco-2 cells. Treatment of the Caco-2 cells with IL-1 beta resulted in a dose- and time-dependent stimulation of IL-6 production with a maximal effect noted at an IL-1 beta concentration of .5 ng/mL at 24 h. IFN-gamma alone did not stimulate IL-6 production but potentiated the effect of IL-1 beta in a synergistic fashion. Treatment of the Caco-2 cells with IL-1 beta induced expression of IL-6 mRNA with a response noticed after 30 min. TNF-alpha and IL-6 did not influence the production of IL-6 in the Caco-2 cells. The results suggest that enterocyte IL-6 production is stimulated by IL-1 beta and that this effect is potentiated by IFN-gamma. The regulation of IL-6 production in the enterocyte may be specific for IL-1 beta, since neither TNF nor IL-6 stimulated IL-6 production.
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PMID:Interleukin-1 beta and interferon-gamma regulate interleukin-6 production in cultured human intestinal epithelial cells. 932 25

To examine the mechanism of steroid resistance in lung fibrosis, cytokines expressed in the lung tissue of mice with bleomycin-induced lung fibrosis were studied. 1. Glucocorticoid administration (1 mg/kg/day) did not affect the grade of lung fibrosis induced by intratracheal injection of bleomycin (3.76 micrograms/g). 2. Cytokines expressed in the lung tissue were studied with the reverse-transcriptase polymerase chain reaction. Levels of promotor cytokines, such as TNF alpha, TGF beta, INF gamma, and IL-2, were significantly higher in lung tissue from the bleomycin group. The expression of these cytokines in the glucocorticoid group was low, especially the peak value. Expression of IL-4 was high in the bleomycin group, and was not inhibited in the glucocorticoid group. Expression of the down-regulator cytokine IL-10 was also high in the bleomycin group and very low in the glucocorticoid group. 3. The non-selectivity of glucocorticoids with respect to promotor and suppressive cytokines may account in part for steroid resistance in bleomycin-induced pulmonary fibrosis.
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PMID:[Steroid resistance and lung-tissue cytokines in experimental bleomycin-induced lung fibrosis]. 934 Dec 82

The experiments described herein were designed to determine whether tumor necrosis factor alpha (TNF-alpha) displays a diurnal variation in various areas of the normal rat brain. TNF-alpha mRNA transcripts were detected by reverse-transcriptase polymerase chain reaction. To monitor diurnal changes in TNF-alpha and alpha-tubulin expression, rats were sacrificed every 4 h for 24 h starting 1 h after light onset; relative mRNA levels were determined for the cerebellum, cortex, hippocampus, hypothalamus and brainstem. TNF-alpha mRNA was higher during the light than in the dark phase in the hypothalamus and hippocampus. alpha-Tubulin mRNA exhibited a similar diurnal variation in the hypothalamus, hippocampus and cortex. In contrast, beta-actin mRNA was lower during the light phase than the dark phase in the hippocampus and cortex. The observed diurnal variations in TNF-alpha mRNA are consistent with the hypothesis that TNF has a physiological role in the brain.
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PMID:Diurnal variations of tumor necrosis factor alpha mRNA and alpha-tubulin mRNA in rat brain. 948 99

Activation of cytosolic phospholipase A2 (cPLA2) by TNF has been shown to be an important component of the signaling pathway leading to cell death. The role of cPLA2 in the cytotoxic action of TNF was investigated in a panel of human leukemic cell lines. TNF could activate cPLA2 only in U937 and HL60 TNF-sensitive leukemic cells, but not in KG1a, CEM, and CEM/VLB100 cells that are relatively resistant to TNF. Pretreatment with 4-bromophenacyl bromide, a cPLA2 inhibitor, rendered U937 and HL60 cell lines resistant to the cytotoxic effect of TNF. Immunoblot and reverse-transcriptase PCR demonstrated that cPLA2 expression was detectable at both transcriptional and translational levels in all leukemic cell lines studied, although CEM and CEM/VLB100 cells expressed cPLA2 mRNA and protein at lower levels. The protein synthesis inhibitor, cycloheximide, increased TNF-induced cPLA2 activity and cytotoxicity in both CEM and CEM/VLB100 cell lines. Low levels of cPLA2 activity in the KG1a cell line could be activated by the cPLA2 activator mellitin, or the calcium ionophore A23187. The data suggest that cPLA2 activity is involved in TNF-induced cytotoxicity in leukemic cells. Resistance to TNF-induced cytotoxicity may involve either protein inhibitors that act upstream of cPLA2 in the TNF-signaling pathway or constitutive defects of cPLA2 itself, possibly involving calcium utilization.
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PMID:Failure to activate cytosolic phospholipase A2 causes TNF resistance in human leukemic cells. 963 6

ICAM-1 is an Ig-like cell adhesion molecule expressed by several cell types, including the endothelium. Cross-linking of ICAM-1 on the surface of different cell types has previously been shown to cause an increase in cellular activation within the cytoplasm. In this study, we have compared signaling events following ligation of ICAM-1 by cross-linking with mAbs with events after activation of HUVEC by TNF. ICAM-1 cross-linking caused activation of Erk-1 and the AP-1 transcription factor complex, without any increase in NF-kappaB activity, in contrast to TNF stimulation. Transcription of VCAM-1 mRNA was observed by reverse-transcriptase PCR after ICAM-1 cross-linking, with no associated transcription of E-selectin. This was reflected by the presence of VCAM-1 protein after immunoprecipitation, without E-selectin expression, in ICAM-1 cross-linked cells. In contrast, mRNA and protein for both VCAM-1 and E-selectin were observed in TNF-treated HUVEC, as expected. Addition of the MEK (MAP/Erk kinase) inhibitor PD98059 reduced expression of VCAM-1 after ICAM-1 cross-linking, suggesting that the Erk pathway is involved in ICAM-1-mediated VCAM-1 expression. In conclusion, ICAM-1-induced expression of VCAM-1 represents a pathway for adhesion molecule up-regulation that is distinct from the TNF-induced pathway. It may be similar to the IL-4 pathway or it may represent a novel pathway.
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PMID:Ligation of ICAM-1 on endothelial cells leads to expression of VCAM-1 via a nuclear factor-kappaB-independent mechanism. 1007 50

To investigate which parameters are stimulated by mineral fibers and whether cigarette smoke enhanced a fiber-induced response, we examined the level of cytokine mRNA from alveolar macrophages (AMs) and lungs of rats exposed to mineral fibers and cigarette smoke in vivo. Male Wistar rats were given a single intratracheal instillation of 2 mg of Union Internationale Contre le Cancer chrysotile or refractory ceramic fiber (RF1). The animals then inhaled a side stream of smoke 5 days per week for 4 weeks. The expression of manganese superoxide dismutase, inducible nitric oxide synthase (iNOS), basic fibroblast growth factor (bFGF), interleukin-1[alpha] (IL-1[alpha]), interleukin-6 (IL-6), and tumor necrosis factor-[alpha] (TNF[alpha]) mRNA from lipopolysaccharide-stimulated AMs and lungs of rats exposed to mineral fibers and/or cigarette smoke were assessed using semiquantitative reverse-transcriptase polymerase chain reaction. Exposure only to cigarette smoke increased in IL-1[alpha] mRNA levels in AMs. Chrysotile stimulated the expression of IL-1[alpha], TNF[alpha], and IL-6 in AMs, and the expression of bFGF in lungs. RF1 resulted in increased expression of IL-1[alpha] and TNF[alpha] in AMs. Cigarette smoke stimulated the gene expression of iNOS in AMs and IL-6 and bFGF in lungs treated with chrysotile; IL-1[alpha] in AMs and bFGF in lungs did the same in lungs with RF1. Among these cytokines, message levels of IL-1[alpha], iNOS, and bFGF were increased in rats stimulated with mineral fibers, and the stimulating effects of mineral fibers were enhanced by cigarette smoke. Therefore, IL-1[alpha], iNOS, and bFGF would be the possible parameters of the lung remodeling induced by mineral fibers.
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PMID:Combined effect of cigarette smoke and mineral fibers on the gene expression of cytokine mRNA. 1033 51

The migration of Langerhans cells is an initial event in the sensitization phase of contact sensitivity. Langerhans cells travel from the epidermis to the regional lymph node, and can be variously modulated in the skin where many cytokines are released from epidermal cells, dermal cells, T helper (Th) cells, and other inflammatory cells during the sensitization and elicitation phase of contact dermatitis, and thus induce an altered inflammatory skin reaction. The modulatory effect of the cytokines released in the skin, such as IL-1beta, GM-CSF, and TNF-alpha as epidermal cytokines, IL-2, IL-12, and IFN-gamma as Th1 type cytokines, and IL-4 and IL-10 as Th2 type cytokines, was analyzed using the chemotactic chamber method in this study. Both GM-CSF and TNF-alpha induced the migration of human Langerhans cells in vitro, whereas IL-1beta, IL-2, IL-10, IL-12, and IFN-gamma had no effect on Langerhans cell migration. In contrast, IL-4 inhibited Langerhans cell migration in a dose dependent manner. The inhibitory activity of IL-4 was reversed by both anti-human IL-4 monoclonal antibody and anti-human IL-4 receptor monoclonal antibody. IL-4 inhibited the Langerhans cell migration induced by both TNF-alpha and GM-CSF. Furthermore, anti-TNF-RII monoclonal antibody inhibited both random migration and the migration induced by TNF-alpha, but not that induced by GM-CSF. A reverse-transcriptase-polymerase chain reaction and fluorescence-activated cell sorter analysis revealed that TNF-alpha up-regulated and IL-4 downregulated the TNF receptor II (TNF-RII) expression of Langerhans cells at both the mRNA and the protein levels. The pretreatment of Langerhans cells with TNF-alpha enhanced the migration of Langerhans cells and the expression of TNF-RII. After pretreating Langerhans cells with TNF-alpha, IL-4 inhibited both the migration of Langerhans cells and the expression of TNF-RII in a time dependent manner. These results indicate that IL-4 inhibits the migratory activity of Langerhans cells by downregulating the expression of TNF-RII in human Langerhans cells and thereby modulates the immune response in the skin.
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PMID:IL-4 inhibits the migration of human Langerhans cells through the downregulation of TNF receptor II expression. 1050 38

Stimulating macrophages with bacterial endotoxin (LPS) activates numerous intracellular signaling pathways that lead to the production of TNF. In this study, we show that four mitogen-activated protein (MAP) kinase pathways are activated in LPS-stimulated macrophages: the extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase/stress-activated protein kinase, p38, and Big MAP kinase (BMK)/ERK5 pathways. Although specific activation of a single MAP kinase pathway produces only a modest effect on TNF promoter activation, activation of each MAP kinase pathway is important for full induction of the TNF gene. Interestingly, a dramatic induction of TNF promoter-driven gene expression was observed when all of the four MAP kinase pathways were activated simultaneously, suggesting a cooperative effect among these kinases. Unexpectedly, cis elements known to be targeted by MAP kinases do not play a major role in multiple MAP kinase-induced TNF gene expression. Rather, a 40-bp sequence harboring the TATA box, is responsible for the gene up-regulation induced by MAP kinases. The proximity of the MAP kinase-responsive element to the transcriptional initiation site suggested that MAP kinases regulate the transcriptional initiation complex. Utilizing alpha-amanitin-resistant RNA polymerase II mutants with or without a C-terminal domain (CTD) deletion, we found that deleting the CTD to 31 tandem repeats (Delta31) led to >90% reduction in MAP kinase-mediated TNF production. Thus, our data demonstrate coordination of multiple MAP kinase pathways in TNF production and suggest that the CTD of RNA polymerase II is required to execute MAP kinase signaling in TNF expression.
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PMID:Regulation of TNF expression by multiple mitogen-activated protein kinase pathways. 1084 89

Interleukin-1 (IL-1) mediates symptoms of sickness during the host response to infection. IL-1 exerts its effects via several subtypes of receptors. To assess the role of IL-1 receptor type I (IL-1RI) in the sickness-inducing effects of IL-1, IL-1beta and the cytokine inducer lipopolysaccharide were administered to IL-1RI-deficient mice (IL-1RI-/-). Sickness was assessed by depression of social exploration, anorexia, immobility and body weight loss. IL-1RI-/- mice were resistant to the sickness-inducing effects of IL-1beta administered intraperitoneally (2 microg/mouse) and intracerebroventricularly (2 ng/mouse), but still fully responsive to lipopolysaccharide administered intraperitoneally (2.5 microg/mouse) and intracerebroventricularly (3 ng/mouse). The sensitivity of IL-1RI-/- mice to lipopolysaccharide was not due to a higher brain expression of proinflammatory cytokines other than IL-1, since lipopolysaccharide-induced expression of brain IL-1 beta, tumour necrosis factor-alpha (TNF-alpha) and IL-6 transcripts were identical in IL-1RI-/- and control mice when measured by semiquantitative reverse-transcriptase polymerase chain reaction 1 h after treatment. Blockade of TNF-alpha action in the brain by intracerebroventricular administration of a fragment of the soluble TNF receptor, TNF binding protein (3.6 microg/mouse), attenuated the depressive effects of intraperitoneal injection of lipopolysaccharide (1 microg/mouse) on behaviour in IL-1RI-/- but not in control mice. Since IL-1RI-/- mice were not more sensitive to intracerebroventricularly TNF-alpha (50 ng) than control mice, these results indicate that IL-1RI mediates the sickness effect of IL-1 and that TNF-alpha simply replaces IL-1 when this last cytokine is deficient.
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PMID:Role of interleukin-1beta and tumour necrosis factor-alpha in lipopolysaccharide-induced sickness behaviour: a study with interleukin-1 type I receptor-deficient mice. 1112 55

We describe the use of non-traditional methods of probe synthesis and quantification and detection of hybridization that appreciably improved non-radioactive in situ hybridization (ISH) in human airway tissue. To avoid the problems of bacterial cloning, plasmid digestion, and probe hydrolysis, we synthesised complementary RNA probes (riboprobes) for ISH from PCR-generated DNA. DNA template was produced by nested PCR incorporation of T7 and SP6 RNA polymerase promoters. We then compared the efficiency of in vitro transcription from PCR-generated template with traditional plasmid template by quantifying the relative probe fluorescence in denaturing gels. Transcription with SP6 or T7 polymerase in either orientation produced TNF riboprobes from a single PCR-generated template more efficiently than from plasmid, providing there were no primer hairpin loops. Fluorescence quantification enabled equal amounts of probe label to be used in ISH, eliminating signals from the sense probe and demonstrating that probes transcribed from PCR templates were as sensitive as hydrolyzed probe transcribed from plasmid. Detection of ISH by a conventional anti-hapten, alkaline phosphatase-based technique was found to cause tissue damage due to extended substrate incubation at high pH. We therefore developed a four-layer, avidin-biotin-peroxidase technique that afforded greater sensitivity, allowing brief substrate incubation and resulting in structural preservation of tissue.
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PMID:Improvement of non-radioactive in situ hybridization in human airway tissues: use of PCR-generated templates for synthesis of probes and an antibody sandwich technique for detection of hybridization. 1189 7


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