UNIPROT:P05231 - FACTA Search

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Query: UNIPROT:P05231 (interleukin-6)
23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Positive inflammatory reactions in an aggressive phenotype are typical features of renal cell carcinoma (RCC). Although a high blood level of inflammatory cytokines, such as interleukin-6, interleukin-8, and tumor necrosis factor-alpha, has been observed in these patients, the mechanisms underlying this clinical phenomenon remain to be elucidated. CCAAT/enhancer binding protein (C/EBP) family are transcription factors which play a role in cell differentiation and inflammatory reactions. Among these, C/EBP-beta induces a variety of cytokines and thus may play a role in the pathogenesis of RCC. We studied the activation of C/EBP-beta determined by electrophoretic mobility shift assay in nine RCC cell lines and 44 tissue samples. Six cell lines showed an activation of C/EBP-beta, whereas three cell lines did not, and two of these three had no expression at all of C/EBP-beta protein. Of 44 tissue samples, 12 (27.3%) showed a >200% increase in the activity compared with the corresponding normal kidney tissues. Locally advanced cases had a significantly higher rate of increased C/EBP-beta activity (5 of 8 = 62.5% in advanced cases versus 7 of 36 = 19.4% in localized cases). Especially, all four cases with renal vein invasion had an increased C/EBP-beta activity. These data suggest that the increased activation of C/EBP-beta may contribute to promote tumor invasiveness and render a malignant phenotype of RCC, although it needs to be validated in a larger series.
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PMID:Increased activation of CCAAT/enhancer binding protein-beta correlates with the invasiveness of renal cell carcinoma. 1263 1

Chlamydia pneumoniae is an obligate intracellular eubacterium and a common cause of acute and chronic respiratory tract infections. This study was designed to show the effect of C. pneumoniae on transcription factor activation in epithelial cells. The activation of transcription factors by C. pneumoniae was determined in human epithelial cell lines (HL and Calu3) by electrophoretic DNA mobility shift assay, Western blotting, and luciferase reporter gene assay. The activation of transcription factors was further confirmed by immunostaining of C. pneumoniae-infected HL cells and mock-infected controls. The effect of transcription factors on C. pneumoniae-induced host cell proliferation was assessed by [(3)H]thymidine incorporation and direct cell counting in the presence and absence of antisense oligonucleotides targeting transcription factors or the glucocorticoid receptor (GR) antagonist RU486. The activation of the GR, CCAAT-enhancer binding protein (C/EBP), and NF-kappaB was induced within 1 to 6 h by C. pneumoniae. While the interleukin-6 promoter was not activated by C. pneumoniae, the GR-driven p21((Waf1/Cip1)) promoter was increased 2.5- to 3-fold over controls 24 h after infection. C. pneumoniae dose-dependently increased the DNA synthesis of the host cells 2.5- to 2.9-fold, which was partly inhibited either by RU486 or by NF-kappaB antisense oligonucleotides. Furthermore, we provide evidence that heat-inactivated C. pneumoniae does not cause a significant increase in cell proliferation. Our results demonstrate that C. pneumoniae activates C/EBP-beta, NF-kappaB, and the GR in infected cells. However, only NF-kappaB and the GR were involved in C. pneumoniae-induced proliferation of epithelial cells.
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PMID:Chlamydia pneumoniae activates epithelial cell proliferation via NF-kappaB and the glucocorticoid receptor. 1450 May 3

In recent studies, sodium arsenite (SA) inhibited IL-6 production in cultured intestinal epithelial cells, at least in part by downregulating the activity of nuclear factor-kappaB (NF-kappaB). The influence of SA on the activity of other transcription factors regulating the interleukin-6 (IL-6) gene in enterocytes is not known. We tested the effect of SA on the activity of CCAAT/enhancer binding protein (C/EBP), activating protein-1 (AP-1), and CRE binding proteins in IL-1beta-treated Caco-2 cells. DNA binding activity was determined by electrophoretic mobility shift assay (EMSA) and transcriptional activity by transfecting cells with luciferase reporter plasmids containing promoter constructs with binding sites for the individual transcription factors. DNA binding activity for all three transcription factors was increased after treatment with SA or IL-1beta. In contrast, SA inhibited transcriptional activity of AP-1 and CRE binding proteins but not C/EBP. Additional experiments provided evidence that the inhibition of AP-1 and CRE mediated transcriptional activity was associated with, and probably caused by, increased expression of the transcriptional repressor cyclic AMP response element modulator (CREM)alpha. The present results are consistent with the concept that SA inhibits IL-6 production in stimulated enterocytes by downregulating the transcriptional activity of several, but not all, IL-6-related transcription factors. Because of the multiple important biological functions of IL-6 in the enterocyte and gut mucosa, methods to regulate enterocyte IL-6 production have significant clinical implications.
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PMID:Sodium arsenite downregulates transcriptional activity of AP-1 and CRE binding proteins in IL-1beta-treated Caco-2 cells by increasing the expression of the transcriptional repressor CREMalpha. 1452 96

The cytokine interleukin-6 (IL-6) plays key roles in the immune and inflammatory responses, acute-phase reaction and hematopoiesis. Such biological actions of IL-6 are characterised by both the activation and the inhibition of gene transcription. Unfortunately, in contrast to gene activation, the mechanism by which IL-6 suppresses transcription remains largely unclear. We have, therefore, investigated this aspect using the Xenopus laevis CCAAT/enhancer binding protein-alpha (C/EBPalpha) gene promoter as a model. We show by transient transfection assays of various promoter-luciferase DNA constructs into hepatoma cells that a C/EBP recognition sequence in the proximal promoter region is essential for the IL-6-mediated repression. Electrophoretic mobility shift assays showed that C/EBPalpha was the major protein that bound to this site and, consistent with its expression pattern, the binding was reduced when the cells were exposed to IL-6. Co-transfection assays revealed for the first time that the ability of C/EBPalpha, but not C/EBPbeta or Sp1, to transactivate the promoter was decreased dramatically when the cells were incubated with IL-6. These studies, therefore, identify a novel mechanism for IL-6-mediated repression of gene transcription that involves a reduction in C/EBPalpha-mediated activation.
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PMID:Interleukin-6 represses the transcription of the CCAAT/enhancer binding protein-alpha gene in hepatoma cells by inhibiting its ability to autoactivate the proximal promoter region. 1462 5

CCAAT/enhancer binding proteins (C/EBP) alpha, -beta and -delta play an important role in mediating I interleukin-6 (IL-6) dependent expression of acute-phase protein (APP) genes in liver during acute-phase (AP) response. Based on the presence of type IL-6 responsive element (IL-6 RE) in the rat haptoglobin (Hp) gene promoter we assumed that some C/EBPalpha, -beta and/or -delta isoforms could mediate the expression of this gene during turpentine-induced AP response. By Western immunoblot and Northern blot assays, we found that turpentine treatment of rats led to a coordinate induction of C/EBPbeta and -delta as well as repression of C/EBPalpha isoforms pool levels in rat liver nuclear extracts (NEs) which was preceded by an adequate alteration of their mRNAs expression in liver. Consequently, results of DNA affinity chromatography revealed that affinity of certain C/EBPalpha isoforms to bind the type I IL-6 RE within the rat Hp gene promoter decreased whereas affinities of certain C/EBPbeta isoforms and C/EBPdelta were increased and induced, respectively. Our data suggest that turpentine-induced alterations of C/EBPalpha, -beta and -delta pool levels and DNA-binding activities can be regarded as an integral part of activation of the Hp gene expression in the course of AP response.
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PMID:Expression of the rat liver haptoglobin gene is mediated by isoforms of C/EBPalpha, -beta and -delta proteins. 1466 30

AMP-activated protein kinase (AMPK) is tightly regulated by the cellular AMP:ATP ratio and plays a central role in the regulation of energy homeostasis and metabolic stress. A pharmacological activator of AMPK, 5-amino-4-imidazole carboxamide riboside (AICAR) inhibited lipopolysaccharide (LPS)-induced expression of proinflammatory cytokines (tumor necrosis factor alpha, interleukin-1beta, and interleukin-6) and inducible nitric oxide synthase in primary rat astrocytes, microglia, and peritoneal macrophages. AICAR attenuates the LPS-induced activation of nuclear factor kappaB via downregulation of IkappaB kinase alpha/beta activity. It also inhibits nuclear translocation of CCAAT/enhancer-binding protein (C/EBP) transcription factor by inhibiting the expression of C/EBP-delta in brain glial cells. The dominant negative form of AMPKalpha2 (D157A) and its antisense documents a possible role of AMPK in the regulation of the cellular proinflammatory process. AICAR also inhibited the production of inflammatory mediators in serum and their expression in CNS of rats injected with a sublethal dose of LPS by intraperitoneal injection. These observations in cultured cells as well as in the animal model suggest that AICAR may be of therapeutic value in treating inflammatory diseases.
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PMID:5-aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside inhibits proinflammatory response in glial cells: a possible role of AMP-activated protein kinase. 1472 46

The CCAAT-enhancer binding protein (C/EBP) family of transcription factors, particularly C/EBPdelta, is well known to regulate or co-regulate a wide range of inflammatory mediators and mechanisms in the periphery, including interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha). These cytokines, in turn, can induce C/EBPdelta expression and translocation to the nucleus as an active transcription factor. Because IL-1, IL-6, and TNF-alpha are increased in pathologically vulnerable regions of the Alzheimer's disease (AD) brain, we sought to determine if C/EBPdelta might be expressed in AD cortex. Immunohistochemistry of AD tissue sections revealed profuse C/EBPdelta staining of astrocytes, particularly reactive astrocytes surrounding amyloid beta peptide deposits. Substantially less immunoreactivity was observed in comparable sections from nondemented elderly control (ND) patients. These qualitative findings were consistent with quantitative Western blot densitometry results showing significant increases in C/EBPdelta in AD compared to ND cortex samples. Additional in vitro studies were pursued in order to characterize functional activity of C/EBPdelta in human elderly astrocytes. Consistent with a functionally active transcription factor, C/EBPdelta immunoreactivity predominated in the nucleus of cultured AD and ND astrocytes, and exhibited increases and nuclear localization, as determined by Western blots and electrophoretic mobility shifts after exposure to C/EBPdelta-inducing cytokines.
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PMID:CCAAT/enhancer binding protein delta (C/EBPdelta) expression and elevation in Alzheimer's disease. 1521 23

Expression of cyclooxygenase-2 (COX-2) has been reported to be elevated in human colorectal adenocarcinoma and other tumors, including those of breast, cervical, prostate, and lung. Genetic knock-out or pharmacological inhibition of COX-2 has been shown to protect against experimentally-induced carcinogenesis. Results from epidemiological and laboratory studies indicate that regular intake of selective COX-2 inhibitors reduces the risk of several forms of human malignancies. Thus, it is conceivable that targeted inhibition of abnormally or improperly elevated COX-2 provides one of the most effective and promising strategies for cancer chemoprevention. The COX-2 promoter contains a TATA box and binding sites for several transcription factors including nuclear factor-kappaB (NF-kappaB), nuclear factor for interleukin-6/CCAAT enhancer-binding protein (NF-IL6/C/EBP) and cyclic AMP response element (CRE) binding protein. Upregulation of COX-2 is mediated by a variety of stimuli including tumor promoters, oncogenes, and growth factors. Stimulation of either protein kinase C (PKC) or Ras signaling enhances mitogen-activated protein kinase (MAPK) activity, which, in turn, activates transcription of cox-2. Celecoxib, the first US FDA approved selective COX-2 inhibitor, initially developed for the treatment of adult rheumatoid arthritis and osteoarthritis, has been reported to reduce the formation of polyps in patients with familial adenomatous polyposis. This COX-2 specific inhibitor also protects against experimentally-induced carcinogenesis, but the underlying molecular mechanisms are poorly understood. The present review covers the signal transduction pathways responsible for regulating COX-2 expression as novel molecular targets of chemopreventive agents with celecoxib as a specific example.
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PMID:Signal transduction pathways regulating cyclooxygenase-2 expression: potential molecular targets for chemoprevention. 1531 5

Interleukin-6 (IL-6), and the related cytokines IL-11, leukemia inhibitory factor (LIF) and oncostatin M (OSM), are potent stimulators of osteoclastic bone resorption. In the present study, we have addressed the possibility that the neuropeptide vasoactive intestinal peptide (VIP) may regulate the production of and/or sensitivity to the IL-6 family of cytokines in mouse calvarial osteoblasts. VIP stimulated IL-6 mRNA expression and protein release in a time- and concentration-dependent manner, whereas mRNA expression of the IL-6 receptor, as well as mRNA expressions of IL-11, LIF, OSM and their cognate receptors, were unaffected by VIP. In cells transfected with the IL-6 promoter coupled to luciferase, VIP increased transcriptional activity. The effects of VIP were shared by the related neuropeptide PACAP-38, belonging to the same superfamily of neuropeptides, whereas secretin did not have any effect, indicating that the effects were mediated by VPAC2 receptors. The effects of VIP were potentiated by the cyclic AMP phosphodiesterase inhibitor rolipram and mimicked by forskolin, indicating the involvement of the cyclic AMP/protein kinase A pathway. This was further demonstrated by the facts that the stimulatory effect of VIP on luciferase activity could be reversed by the PKA inhibitors H-89 and KT5720 and was mimicked by cyclic AMP analogues selective for PKA, but not by those selective for Epac. In addition, VIP enhanced the phosphorylation of CREB, as assessed by both immunocytochemical analysis and Western blot. The DNA binding activity of nuclear extracts to C/EBP was increased by VIP, whereas binding to AP-1 was decreased. In contrast, DNA binding to NF-kappaB, as well as nuclear translocation of NF-kappaB and C/EBP, were unaffected by VIP. The mRNA expressions of C/EBPbeta, C/EBPdelta, C/EBPgamma, c-Jun, JunB, c-Fos, Fra-1 and IkappaBalpha and protein level of IkappaBalpha were all unaffected by VIP. These observations, together, demonstrate that VIP stimulates IL-6 production in osteoblasts by a mechanism likely to be mediated by VPAC2 receptors and dependent on cyclic AMP/protein kinase A/CREB activation and also involving the transcription factors C/EBP and AP-1.
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PMID:Increased expression of interleukin-6 by vasoactive intestinal peptide is associated with regulation of CREB, AP-1 and C/EBP, but not NF-kappaB, in mouse calvarial osteoblasts. 1608 72

The Serratia marcescens-derived protease serralysin is considered to play an important role in the pathogenesis of infection. Protease-activated receptor 2 (PAR-2) is activated by trypsin and also several other trypsin-like serine proteases, leading to the modulation of inflammatory and immune responses. However, little is known about the activation of PAR-2 by bacterial proteases and its roles in bacterial infection. In this study, we investigated whether S. marcescens serralysin activates host inflammatory responses through PAR-2. Our results demonstrated that serralysin induces interleukin-6 (IL-6) and IL-8 mRNA expression in a human lung squamous cell carcinoma, EBC-l cells. In addition, serralysin activated activator protein 1 (AP-1)-, CCAAT/enhancer-binding protein (C/EBP)-, and nuclear factor-kappaB (NF-kappaB)-driven promoters in EBC-1 cells. An electrophoretic mobility shift assay showed that serralysin activates the binding of AP-1, C/EBPbeta, and NF-kappaB in the cells. Inactivation of serralysin resulted in the failure of transactivation of AP-1-, C/EBP-, and NF-kappaB-driven promoters in the cells. Furthermore, serralysin activated AP-1-, C/EBP-, and NF-kappaB-driven promoters via PAR-2 in HeLa cells. PAR-2 antagonist peptides decreased serralysin-induced transactivation of AP-1-, C/EBP-, and NF-kappaB-driven promoters in EBC-1 cells. Considered together, these results suggest that serralysin requires PAR-2 to activate the critical transcription factors AP-1, C/EBPbeta, and NF-kappaB for host inflammatory responses.
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PMID:Serratia marcescens serralysin induces inflammatory responses through protease-activated receptor 2. 1704 6

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