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

Human C-reactive protein (CRP) is the major acute phase reactant during inflammation. Regulation of CRP gene expression has been studied in two experimental systems: transgenic mice and human hepatoma cells. In the first system the human CRP gene flanked by approximately 10(4) bases of 5' and 3' sequences is expressed in a liver-specific and inducible manner. The chromatin configuration of the CRP transgene is characterized by the presence of constitutive and inducible liver-specific DNase I-hypersensitive sites. Inducible sites map precisely at the level of the CRP promoter region. In hepatoma cells we analysed the expression of the bacterial chloramphenicol acetyltransferase (CAT) gene driven by various segments of the CRP promoter. This latter approach has led to the identification of promoter elements responsive to interleukin-6 and of hepatocyte-specific nuclear proteins that interact with them.
Mol Biol Med 1990 Jun
PMID:Regulation of the human C-reactive protein gene, a major marker of inflammation and cancer. 217 Aug 8

The promoter region of the interleukin-6 (IL-6) gene has a putative NF-kappa B-binding site. We found that a fragment of the IL-6 promoter containing the site specifically binds highly purified NF-kappa B protein and the NF-kappa B protein in nuclear extracts of phorbol ester-induced Jurkat cells. Mutations of the NF-kappa B site abolished complex formation with both purified NF-kappa B and the nuclear extract protein. Transient expression of chloramphenicol acetyltransferase (CAT) plasmids containing the IL-6 promoter revealed very little activity of the promoter in U-937 monocytic cells and in HeLa cells before stimulation. However, stimulation of U-937 and HeLa cells by inducers of NF-kappa B led to a dramatic increase in CAT activity. Mutations in the NF-kappa B-binding site abolished inducibility of IL-6 promoter-cat constructs in U-937 cells by lipopolysaccharide, tumor necrosis factor alpha, the double-stranded RNA poly(IC), or phytohemagglutinin and in HeLa cells by tumor necrosis factor alpha and drastically reduced but did not completely eliminate inducibility in HeLa cells stimulated by double-stranded RNA poly(IC) or phorbol 12-myristate 13-acetate. These results suggest that NF-kappa B is an important mediator for activation of the IL-6 gene by a variety of IL-6 inducers in both U-937 and HeLa cells and that alternative inducible enhancer elements contribute in a cell-specific manner to IL-6 gene induction. Because NF-kappa B is involved in the control of a variety of genes activated upon inflammation, NF-kappa B may play a central role in the inflammatory response to infection and tissue injury.
Mol Cell Biol 1990 May
PMID:Activation of interleukin-6 gene expression through the NF-kappa B transcription factor. 218 31

The cytokine which is now called interleukin-6 (IL-6) has emerged as a major systemic alarm signal produced by essentially every injured tissue in response to almost every kind of damage. The hallmark of IL-6 gene regulation is its induction in many different tissues by inflammation-associated cytokines, bacterial products, virus infection and by activation of any of the three major signal transduction pathways (diacylglycerol, cAMP and Ca2(+)-activated). Many of these inducers act largely through a 23 base-pair "multi-response element" in the IL-6 promoter. Different tissues secrete multiple post-translationally modified forms of IL-6 (six protein species in the size range 23 to 30 kDa, and additional forms of size greater than or equal to 45 kDa). IL-6 plays a key role in activating a variety of host defence mechanisms that are aimed at limiting tissue injury. Thus, IL-6 elicits major changes in the biochemical, physiological and immunological status of the host (e.g. the "acute phase" plasma protein response). IL-6 enhances plasma protein gene expression not only in hepatocytes but also in monocytes, fibroblasts and lymphocytes. Elevated levels of IL-6 are observed in body fluids during acute and chronic infections, neoplasia and autoimmune diseases. The nature of the IL-6 receptor in hepatic and non-hepatic cells, the different signal transduction pathways involved in the regulation of particular liver genes by IL-6, the association between IL-6 levels in body fluids and clinical outcome and between IL-6 haplotypes and specific disease states remain to be explored in detail.
Mol Biol Med 1990 Apr
PMID:Interleukin-6: a regulator of plasma protein gene expression in hepatic and non-hepatic tissues. 218 60

Using variable-length deletion constructs of the 5'-flanking region of the human interleukin-6 (IL-6) gene linked to the chloramphenicol acetyltransferase gene, we showed that the region from positions -109 to -50 mediated the bulk of the response to tumor necrosis factor (TNF) or interleukin-1 (IL-1), while it was less responsive to forskolin. DNA mobility shift assays and DNase I footprinting analysis identified a nuclear protein from TNF- or IL-1-treated fibroblasts that bound to a region comprising a kappa B-like element located between positions -72 and -63 on the IL-6 gene. On the basis of these and other experiments, we conclude that TNF and IL-1 apparently activate IL-6 gene expression by closely related mechanisms involving activation of a NF-kappa B-like factor, whereas the pathway of IL-6 induction by forskolin is, in part, different.
Mol Cell Biol 1990 Jul
PMID:Interleukin-6 induction by tumor necrosis factor and interleukin-1 in human fibroblasts involves activation of a nuclear factor binding to a kappa B-like sequence. 219 63

Expression of the rat alpha 1-acid glycoprotein gene is stimulated by interleukin-1 (IL-1) and interleukin-6 (IL-6) and is synergistically enhanced by the combination of the two. The distal regulatory element (DRE), a 142-base-pair (bp) sequence located 5 kilobase pairs upstream of the transcriptional start site, appears to be crucial for this cytokine response. The cytokine-specific regulatory sequences within the DRE have been identified by inserting individual DRE subregions, selected combinations of these, or a few linker mutated fragments into a plasmid containing an enhancerless simian virus 40 promoter linked to the chloramphenicol acetyltransferase gene. The regulatory activity was determined in transiently transfected human and rat hepatoma cells. The IL-1 response region was confined to the 5'-most 62 bp of the DRE, and its function seemed to depend on at least two separate components. The same region was also responsive to phorbol ester treatment. The IL-6 regulatory function was dependent on a 54-bp sequence located within the 3' half of the DRE. When the IL-1 response region was recombined with the IL-6 regulatory region of the DRE or with IL-6 response elements of other plasma protein genes, a strong cooperative action by IL-1 and IL-6 was achieved. The functional DRE sequences were recognized by nuclear proteins extracted from rat liver and hepatoma cells. However, no cytokine-inducible binding activity was detectable, which suggests that transcriptional regulation through the DRE might be controlled by posttranslational modification of constitutively bound trans-acting factors.
Mol Cell Biol 1990 Aug
PMID:The cytokine response element of the rat alpha 1-acid glycoprotein gene is a complex of several interacting regulatory sequences. 219 41

Interleukin-6 (IL-6) modulates a number of processes relevant to host immunity and inflammation. We investigated the capacity of the human alveolar macrophage to elaborate IL-6 in response to lipopolysaccharide (LPS), recombinant interleukin-1 (rIL-1), and recombinant tumor necrosis factor (rTNF), and compared macrophage IL-6 production to that of blood monocytes and lung fibroblasts. Unstimulated and TNF-stimulated alveolar macrophages and monocytes produced little or no detectable IL-6. In contrast, macrophages and monocytes produced large amounts of IL-6 in response to LPS and monocytes produced lesser but readily detectable amounts in response to rIL-1. Monocytes and alveolar macrophages differed significantly in their capacity to produce IL-6, with macrophages making more IL-6 in response to LPS and less IL-6 in response to rIL-1 than autologous blood monocytes. Monocytes aged in vitro produced little detectable IL-6 in response to LPS or rIL-1, suggesting that differences in cell maturity may account for the diminished capacity of the alveolar macrophage to produce IL-6 in response to IL-1 but not its enhanced capacity to produce IL-6 in response to LPS. Mononuclear phagocytes and lung fibroblasts also differed in their ability to produce IL-6. Lung fibroblasts produced more IL-6 in response to rIL-1 and less IL-6 in response to LPS than monocytes and macrophages. In addition, monocytes and macrophages elaborated electrophoretically identical IL-6 moieties that differed from those produced by lung fibroblasts. These differences could be at least partially attributed to differences in sialylation and/or glycosylation.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1990 Nov
PMID:Human alveolar macrophage and blood monocyte interleukin-6 production. 222 4

Evidence from epidemiological and histopathologic studies in humans with autoimmune type 1 (insulin-dependent) diabetes suggests that beta-cell destruction within the islets of Langerhans progresses through a number of stages. In this review we draw on recent experimental evidence in an attempt to define the molecular pathology of these stages. Stage 1 is postulated to be initiated by modification of the beta cell by virus, chemical or other factors, leading to the production of interferon-alpha, hyperexpression of major histocompatibility complex (MHC) class I molecules and induction of MHC class II molecules. Experiments in transgenic mice suggest that overexpression of MHC molecules is in itself detrimental to beta-cell function. Shedding of antigen(s) from dying beta cells in combination with hyperexpression of MHC molecules may be a powerful immunogenic stimulus. Stage 2 commences with infiltration of the islets by immuno-inflammatory cells (termed insulitis). It is proposed that production of cytokines from the infiltrating cells induces "phenotypic switching" in beta cells, with further upregulation of MHC molecules and the induction of intracellular adhesion molecule-1 expression and interleukin-6 production. Together, these properties are seen as a prerequisite for the presentation of autoantigen by beta cells to adherent T lymphocytes and autoimmune activation. The final stage encompasses autoimmune-mediated destruction of the beta cells by the targeted delivery of cytotoxic cytokines and other mediators.
Mol Biol Med 1990 Aug
PMID:Molecular pathology of type 1 diabetes. 223 44

The feedback inhibition of interleukin-6 (IL-6) gene expression by glucocorticoids represents a regulatory link between the endocrine and immune systems. The mechanism of the efficient repression of the IL-6 promoter by dexamethasone (Dex) was investigated in HeLa cells transiently transfected with plasmid constructs containing different IL-6 promoter elements linked to the herpesvirus thymidine kinase gene (tk) promoter and the bacterial chloramphenicol acetyltransferase gene (cat) and cotransfected with cDNA vectors constitutively expressing either the active wild-type or inactive mutant human glucocorticoid receptor (GR). The induction by interleukin-1, tumor necrosis factor, phorbol ester, or forskolin of IL-6-tk-cat chimeric constructs containing a single copy of the IL-6 DNA segment from -173 to -151 (MRE I) or from -158 to -145 (MRE II), which derive from within the multiple cytokine- and second-messenger-responsive enhancer (MRE) region, was strongly repressed by Dex in a wild-type GR-dependent fashion irrespective of the inducer used. The induction by pseudorabies virus of an IL-6 construct containing the IL-6 TATA box and the RNA start site ("initiator" or Inr element) but not the MRE region was also repressed by Dex in the presence of wild-type GR. DNase I footprinting showed that the purified DNA-binding fragment of GR bound across the MRE, the TATA box, and the Inr site in the IL-6 promoter; this footprint overlapped that produced by proteins present in nuclear extracts from uninduced or induced HeLa cells. Imperfect palindromic nucleotide sequence motifs moderately related to the consensus GR-responsive element (GRE) motif were present at the Inr, the TATA box, and the MRE II site in the IL-6 promoter; although MRE I and a GR-binding site between -201 and -210 in IL-6 both lacked a discernible inverted repeat motif, their sequences showed considerable similarity with negative GRE sequences in other Dex-repressed genes. Surprisingly, chimeric genes containing MRE II, which lacks a recognizable GACGTCA cyclic AMP- and phorbol ester-responsive motif, were strongly induced by both phorbol ester and forskolin, suggesting that MRE II (ACATTGCACAATCT) may be the prototype of a novel cyclic AMP- and phorbol ester-responsive element. Taken together, these observations suggest that ligand-activated GR represses the IL-6 gene by occlusion not only of the inducible IL-6 MRE enhancer region but also of the basal IL-6 promoter elements.
Mol Cell Biol 1990 Nov
PMID:On the mechanism for efficient repression of the interleukin-6 promoter by glucocorticoids: enhancer, TATA box, and RNA start site (Inr motif) occlusion. 223 15

We have cloned the promoter for the human third component of complement (C3) gene and have identified sequences involved in its regulation during the acute-phase response. A construct linking 199 bp of the C3 promoter to the firefly luciferase gene was found to be very responsive to interleukin-1 (IL-1) and modestly responsive to interleukin-6 (IL-6) by transfection analysis in the human hepatoma line Hep3B2. Simultaneous treatment with the two cytokines showed a strong synergy between the actions of the two molecules. A 58-bp fragment (-127 to -70 bp) was shown by 5' and 3' deletional mutagenesis to contain cis-acting elements that mediated both the IL-1 response and the IL-1-plus-IL-6 synergistic response of this promoter. When coupled to a heterologous promoter, this fragment enabled the synergistic induction by IL-1 plus IL-6. Sequences homologous to the palindrome ACATTGCACAATCT, which mediates the induction of the IL-6 gene by IL-1 (S. Akira, H. Isshiki, T. Sugita, O. Tanabe, S. Kinoshita, Y. Nishio, T. Nakajima, T. Hirano, and T. Kishimoto, EMBO J. 9:1897-1906, 1990), and the core sequence of the IL-6-responsive element of the rat alpha 2-macroglobulin gene (CTGGGA; M. Hattori, L. J. Abraham, W. Northemann, and G. H. Fey, Proc. Natl. Acad. Sci. USA 87:2364-2368, 1990) are contained within this fragment in immediate juxtaposition and partially overlapping. Site-directed mutagenesis within this homology region drastically reduced the inducibility of the C3 promoter by either cytokine. DNase I footprinting analysis defined a binding site for the transcription factor CCAAT/enhancer-binding protein (C/EBP), which included the IL-1-responsive element-like sequence. No differences were seen between the footprints generated by using extracts from unstimulated and IL-1-stimulated Hep3B2 cells. However, gel retardation analyses revealed two IL-1-specific bands. The data suggest that the induction by IL-1 is mediated by a factor belonging to the family of C/EBP-related proteins.
Mol Cell Biol 1990 Dec
PMID:A 58-base-pair region of the human C3 gene confers synergistic inducibility by interleukin-1 and interleukin-6. 224 55

Interleukin-6 (IL-6) is one of the major mediators of inflammation, and its expression is inducible by the other inflammatory lymphokines, interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-alpha). We demonstrate that a common IL-6 promoter element, termed inflammatory lymphokine-responsive element (ILRE), is important for induction of IL-6 gene expression by IL-1 and TNF-alpha despite possible differences in the mechanisms of action of these lymphokines. Remarkably, the ILRE sequence, located between -73 to -63 relative to the mRNA cap site, is highly homologous to NF-kappa B transcription factor-binding motifs and binds an IL-1-TNF-alpha-inducible nuclear factor; the sequence specificities, binding characteristics, and subcellular localizations of this factor are indistinguishable from those of NF-kappa B. In addition, mutations of the ILRE sequence which impair the binding of this nuclear factor abolished the induction of IL-6 gene expression by IL-1 and TNF-alpha in vivo. These results indicate that a nuclear factor indistinguishable from NF-kappa B is involved in the transcriptional activation of the IL-6 gene by IL-1 and TNF-alpha.
Mol Cell Biol 1990 Feb
PMID:Involvement of a NF-kappa B-like transcription factor in the activation of the interleukin-6 gene by inflammatory lymphokines. 240 50


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