Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 5'-flanking region (-2024 to +61) of the guinea pig liver transglutaminase gene and some 5'-deletion mutants were tested for promoter activity in human hepatoblastoma HepG2 cells treated with interleukin-6 (IL-6) by an assay of the transient expression of the chloramphenicol acetyltransferase reporter gene. The promoter activity of the 5'-flanking region introduced into the HepG2 cells was increased by IL-6.
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PMID:Increase caused by interleukin-6 in promoter activity of guinea pig liver transglutaminase gene. 776 54

Human TR3 orphan receptor is a member of the steroid/thyroid hormone receptor superfamily and is the human homologue of the proteins encoded by the rat NGFI-B and mouse nur77 genes. These genes are induced rapidly by androgens/growth factors and may have functions related to cell proliferation, differentiation, and apoptosis. To investigate the TR3 orphan receptor gene transcriptional regulation, a 2.3-kilobase genomic DNA fragment containing the TR3 orphan receptor gene promoter region was isolated, sequenced, and characterized. Sequence homology search within this promoter region revealed some potential cis-acting elements such as cAMP response element, interleukin-6 response element, estrogen response element, and GC box. Deletion analysis and chloramphenicol acetyltransferase assay also showed a novel cis-acting element of TR3 orphan receptor gene (NCAE-TR3), 200-181 base pairs upstream of the transcriptional start site. Gel retardation assay further demonstrated that some nuclear factors can bind to this NCAE-TR3. Together, our data suggest that NCAE-TR3 could be a new enhancer element associated with the transcription of an early response gene for mitogenesis and apoptosis.
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PMID:Identification of a new enhancer in the promoter region of human TR3 orphan receptor gene. A member of steroid receptor superfamily. 789 Jun 57

Redox-based modulation plays a role in transcriptional control of gene expression. In the present study, we investigated the possible role of reactive oxygen species in the induction of interleukin-6 (IL-6) mRNA and in increases in NF kappa B binding activity by tumor necrosis factor (TNF) alpha using a mouse fibroblastic cell line, Balb/3T3. Expression of IL-6 mRNA is known to be dependent upon NF kappa B that binds to the 5'-flanking region of the IL-6 gene. We found that: (i) TNF alpha increased IL-6 mRNA levels and this increase was inhibited by N-acetyl-L-cysteine (NAC), a scavenger of reactive oxygen species. (ii) NF kappa B binding activity in this cell line was also increased by TNF alpha, and the increase was inhibited in the presence of NAC. (iii) The treatment of cells with low doses of hydrogen peroxide increased the NF kappa B binding activity. (iv) Expression of a reporter gene in which the chloramphenicol acetyltransferase (CAT) gene was under the control of NF kappa B binding sites was induced by hydrogen peroxide. These results suggest that the induction of IL-6 mRNA is regulated by a mechanism involving reactive oxygen species and that NF kappa B, whose activity is sensitive to the cellular redox state, plays an important role in this induction in a fibroblastic cell line, Balb/3T3, stimulated with TNF alpha.
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PMID:Inhibition by N-acetyl-L-cysteine of interleukin-6 mRNA induction and activation of NF kappa B by tumor necrosis factor alpha in a mouse fibroblastic cell line, Balb/3T3. 792 24

Freshly isolated leukemic cells from patients with adult T-cell leukemia (ATL) and human T-cell leukemia virus type I (HTLV-I)-infected T-cell lines constitutively produce high levels of interleukin-6 (IL-6) protein and mRNA. To clarify the mechanisms that lead to the activation of IL-6 gene in HTLV-I-infected cells, we first studied the regulatory regions in the IL-6 gene transcription by transfection of chloramphenicol acetyltransferase (CAT) reporter plasmids containing the IL-6 promoter. When transfected into HTLV-I-infected T-cell lines MT-2 and HUT-102, IL-6 promoter/CAT plasmids were strongly activated without any stimulation. By deletion analysis of 5' upstream region of IL-6 promoter, the DNA region between -73 and -59 bp from the transcription start site of IL-6 gene was important in the expression of IL-6/CAT activities in HTLV-I-infected cells. This region contains nuclear factor (NF)-kappa B binding site. The site-directed mutation of the kappa B motif in IL-6/CAT plasmid resulted in the complete abrogation of IL-6 promoter activity in these cells. Furthermore, when IL-6 promoter/CAT plasmid was introduced into an HTLV-I-uninfected T-cell line, Jurkat, IL-6 promoter activity was silent in the basal level, but strongly increased by the cotransfection with an HTLV-I tax expression plasmid. However, tax expression plasmid showed no transactivation activity, when kappa B site was mutated in IL-6 promoter/CAT plasmid. We found that the IL-6 kappa B site specifically formed a complex with NF-kappa B-containing nuclear extracts from MT-2 and HUT-102 cells. Finally, transfection of HTLV-I tax into Jurkat cells resulted in induction of specific binding of nuclear extracts to the NF-kappa B sequence. These results strongly suggest that HTLV-I tax gene may transactivate IL-6 gene through kappa B site in HTLV-I-positive T-cell lines and activation of NF-kappa B may be crucial in HTLV-I-induced IL-6 gene activation in ATL.
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PMID:Transcriptional regulation of the human interleukin-6 gene promoter in human T-cell leukemia virus type I-infected T-cell lines: evidence for the involvement of NF-kappa B. 794 64

Revealing the regulatory mechanisms involved in P-glycoprotein expression is important to our understanding of multidrug resistance (MDR) in tumor cells. The MDR1 gene encoding P-glycoprotein contained a promoter sequence (-157 to -125) that was found to be homologous with other mdr gene promoters and that specifically interacted with a nuclear protein. The nuclear protein was identified, using a HeLa lambda gt11 cDNA expression library, to be the transcriptional regulator nuclear factor for interleukin-6 (NF-IL6), a member of the C/EBP family of transcription factors that bound an NF-IL-6-like consensus element 5'-TTTCGCAGT-3'. Furthermore, a glutathione S-transferase fusion protein (10.1-glutathione S-transferase) containing the partial NF-IL6 cDNA was also found to specifically interact with the MDR1 promoter sequence. Co-transfection of an NF-IL6 expression vector with a chloramphenicol acetyltransferase reporter gene driven by 1018 base pairs of MDR1 5'-flanking sequences demonstrated that NF-IL6 trans-activated the MDR1 promoter. This trans-activation was significantly reduced when the NF-IL6 element in the reporter gene construct was deleted or mutated. Identification of NF-IL6 as an important transcriptional regulator and the implications of its potential role in MDR1 gene induction in response to a variety of stimuli are discussed.
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PMID:NF-IL6, a member of the C/EBP family of transcription factors, binds and trans-activates the human MDR1 gene promoter. 796 62

Interleukin-6 (IL-6) stimulates the release of hCG from syncytiotrophoblast cells, but the effects of IL-6 and other cytokines on the release of placental lactogen (hPL) are unknown. To determine the effect of IL-6 on hPL release, we exposed an enriched fraction of trophoblast cells (prepared by the isopycnic centrifugation of enzymatically dispersed term placenta) continuously to IL-6 (500 U/ml) for up to 6 days. The amounts of hPL released by the IL-6-exposed cells during days 3 and 6 were 177.6 +/- 2.4% and 267.5 +/- 12.6% that of control cells, respectively (P < 0.0001 in each instance). In addition, the hPL messenger RNA (mRNA) contents of the IL-6-exposed cells after 3 and 6 days of exposure were 2.2- and 4.7-fold that of control cells. The stimulatory effect of IL-6 on hPL release and hPL mRNA levels was dose dependent, with a minimal effective dose of 50 U/ml. IL-1 beta, which is known to stimulate IL-6 production by human trophoblast cells, also stimulated dose-dependent increases in hPL release and hPL mRNA levels. IL-6 (500 U/ml) had no effect on trophoblast differentiation, but stimulated a 20-fold increase in hPL promoter activity in BeWo choriocarcinoma cells transfected transiently with a plasmid containing 2.3 kilobases of the hPL promoter coupled to the chloramphenicol acetyltransferase gene. In addition, BeWo cells exposed to IL-6 (500 U/ml) for 3 and 6 days contained 2.4- and 3.2-fold more hPL mRNA levels than control cells. Because placental macrophages and syncytiotrophoblast cells release IL-6, these results strongly suggest an autocrine/paracrine role for IL-6 in the regulation of hPL release. The increase in hPL release appears to be due at least in part to an increase in hPL gene expression.
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PMID:Interleukin-6 stimulates placental lactogen expression by human trophoblast cells. 803 20

Interleukin-6 (IL-6) is a multifunctional cytokine that regulates both humoral and cellular immune responses. Accumulating evidence suggests that the infection of T cells and other cell types with human T-lymphotropic virus type 1 (HTLV-1) results in the constitutive expression of IL-6. However, the underlying molecular mechanisms are little understood. When a reporter plasmid, pIL6-CAT-E3, in which the human IL-6 enhancer/promoter region from -630 to +14 was linked to the bacterial chloramphenicol acetyltransferase (CAT) gene, was transfected, HTLV-1-infected but not -uninfected T-cell lines activated the IL-6 promoter. This indicated the presence of a factor transactivating the IL-6 gene in the infected cells. To evaluate the involvement of the HTLV-1-encoded transacting factor (Tax) in this transactivation, we examined the effect of transient cotransfection with the Tax-expression plasmid, pMAX-Neo, on the transcription from the IL-6 promoter by use of COS1 cells. The cotransfected COS1 has about six-times greater the CAT activity than that transfected with pIL6-CAT-E3 alone. The analysis of a series of deletions of the IL-6 promoter suggested that the region (-105/-47) containing a NF kappa B site was crucial for the Tax responsiveness. We further examined the effect of Tax on endogenous IL-6 gene expression using the Jurkat clone, JPX-9, stably transfected with pMAX-Neo. JPX-9 accumulated steady state transcripts of the endogenous IL-6 gene in response to the induction of Tax expression. Our findings indicate an important role of the Tax protein in the expression of IL-6 in cells infected with HTLV-1.
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PMID:Transactivation of the human interleukin-6 gene by human T-lymphotropic virus type 1 Tax protein. 806 47

A high level of plasma fibrinogen has been shown to be an important risk factor for myocardial infarction and stroke. Thus, we were prompted to investigate regulation of human fibrinogen biosynthesis, a process wherein expression of the B beta-chain of fibrinogen appears to be rate-limiting for fibrinogen secretion. Using electrophoretic mobility shift assays with synthetic probes representing portions of the human B beta-fibrinogen promoter, we have defined several elements that bind distinct classes of transcription factors present in human hepatoma cell nuclear extracts. The contribution of each element to promoter activity was demonstrated in transfection experiments using promoter-chloramphenicol acetyltransferase constructs and human hepatoma cells. Our observations indicate that two distinct sequence elements are required for maximal induction of transcription by interleukin-6. One of these sequences is an IL-6-RE core element similar to that reported for the rat alpha 2-macroglobulin promoter and the other is a binding site for the C/EBP family of transcription factors. We also report two additional elements, one negative- and one positive-acting, that bind novel sequence-specific factors.
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PMID:Functional characterization of promoter elements involved in regulation of human B beta-fibrinogen expression. Evidence for binding of novel activator and repressor proteins. 822 73

To understand the molecular mechanisms underlying the regulation of hepatocyte growth factor (HGF) gene expression and to define the DNA sequences essential for its cell-type specific and inducible expression, we have isolated and characterized the 5'-flanking region of the HGF gene. A genomic clone containing 2.8 kilobases of the 5'-flanking region of the HGF gene has been isolated from a mouse liver genomic library. Sequence analysis showed that the promoter region of the mouse HGF gene contains a noncanonical TATA box (ATAAA). Further analysis of the 5'-flanking region revealed a number of putative regulatory elements, such as four interleukin-6 response elements (IL-6 RE), two potential binding sites for NF-IL6, a TGF-beta inhibitory element (TIE), a cAMP response element (CRE), two estrogen response elements (ERE) including one located in the first intron, a potential vitamin D response element (VDRE) which overlaps a chicken ovalbumin upstream promoter (COUP) transcription factor binding element, two liver-specific transcription factor (C/EBP) binding sites, and a B cell- and macrophage-specific transcriptional factor binding site (PU.1/ETS). To determine the location of sites that may be critical for the function of the HGF promoter, we constructed a series of chimeric genes containing variable regions of the 5'-flanking sequence of HGF gene and the coding region for chloramphenicol acetyltransferase (CAT). Transient transfection of chimeric plasmids demonstrated that the mouse HGF gene promoter containing 70 base pairs of the 5'-flanking sequences were active in mouse fibroblast NIH 3T3 cells and in human endometrial carcinoma RL95-2 cells. This basal transcription activity of the HGF promoter was modulated in NIH 3T3 and RL95-2 cells by multiple upstream elements. Three positive elements were identified at positions -2848 to -2674, -1386 to -1231, and -699 to -274, and three negative candidate elements were mapped to positions -1652 to -1386, -964 to -699, and -274 to -70, respectively. By the combination of a series of 5'-end deletion and internal deletion, a cell type-specific negative regulatory element in RL95-2 cells was localized to the nucleotide position -964 to -699. Moreover, the reporter plasmid containing interleukin 6 (IL-6) response element was responsive to IL-6 stimulation in stably transfected NIH 3T3 cells. Our findings revealed a complex pattern of transcriptional regulation of the mouse HGF gene expression.
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PMID:Structural and functional characterization of the mouse hepatocyte growth factor gene promoter. 830 76

Serum concentration of rat T1 kininogen increases 20- to 30-fold in response to acute inflammation, an induced hepatic synthesis regulated primarily at the transcriptional level. We have demonstrated by transient transfection analyses that rat T1 kininogen gene/chloramphenicol acetyltransferase (T1K/CAT) constructs are highly responsive to interleukin-6 and dexamethasone. In these studies we examined the regulation of a highly homologous K kininogen gene promoter and showed that it is minimally induced under identical conditions. The basal expression of the KK/CAT construct was, however, five- to sevenfold higher than that of the analogous T1K/CAT construct. Promoter-swapping experiments to examine the molecular basis of this differentially regulated basal expression showed that at least two K kininogen promoter regions are important for conferring its high basal expression: a distal 19-bp region (C box) constituted a binding site for C/EBP family proteins, and a proximal 66-bp region contained two adjacent binding sites for hepatocyte nuclear factor 3 (HNF-3). While the C box in the K kininogen promoter was able to interact with C/EBP transcription factors, the T1 kininogen promoter C box could not. In addition, HNF-3 binding sites of the K kininogen promoter demonstrated stronger affinities than those of the T1 kininogen promoter. Since C/EBP and HNF-3 are highly enriched in the liver and are known to enhance transcription of liver-specific genes, these differences in their binding activities thus accounted for the K kininogen gene's higher basal expression. Our studies demonstrated that evolutionary divergence of a few critical nucleotides may lead to subtle changes in the binding affinities of a transcription factor to its recognition site, profoundly altering expression of the downstream gene.
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PMID:Molecular analysis of the differential hepatic expression of rat kininogen family genes. 841 71


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