Transcriptional Control of Liver Acute Phase Genes by Interleukin-6 and Leukemia Inhibitory Factor

Hocke, Gertrud M.; Baffet, Georges; Cui, Mei‐Zhen; Brechner, Thomas; Barry, David I.; Goel, Akul; Fletcher, R. G.; Abney, Charles C.; Hattori, Masahira; Fey, H.

doi:10.1007/978-3-642-76412-7_12

Cited by 8 publications

(16 citation statements)

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“…Leukemia-inhibitory factor was recently shown to induce the same set of acute-phase protein genes in hepatocytes as does IL-6 (9, 10). In HepG2 cells, leukemia-inhibitory factor stimulates the rat a2-macroglobulin promoter in transient transfection studies (30). To corroborate the importance of APRF in the regulation of ao2-macroglobulin gene expression, we examined whether leukemia-inhibitory factor is similarly able to induce APRF in HepG2 cells.…”

Section: Resultsmentioning

confidence: 99%

“…Similarly, the acutephase response element (APRE) of the rat a2-macroglobulin promoter, localized by us and others, is composed of two such hexanucleotide motifs which functionally cooperate to confer the full IL-6 response of the promoter (28,30,34,38). Regulatory elements containing the CTGGGA hexanucleotide were thought to be implicated mainly in the regulation of class 2 acute-phase protein genes (30,31). However, homologous elements were demonstrated to be required for the induction of the class 1 acute-phase haptoglobin and ae-acid glycoprotein genes by 63).…”

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confidence: 97%

“…This factor, termed IL-6 RE-BP, was induced maximally 4 to 18 h after IL-6 stimulation, and its appearance was shown to depend on ongoing protein synthesis. The apparent molecular size of IL-6 RE-BP was estimated to be 46 kDa in Southwestern (DNA-protein) blotting and UV cross-linking experiments (30). More recently, the same authors reported a molecular size of 102 + 10 kDa on the basis of further UV cross-linking experiments (31).…”

mentioning

confidence: 98%

“…More recently, cloning of an additional member of the C/EBP gene family, termed NF-IL6fi, was reported (36). Expression of NF-IL61, like expression of NF-IL6, is induced by cyto-kines, and the protein has been shown to heterodimerize and nuclear factor in human hepatoma cells which binds to the APRE and is likely to be the human homolog of the APREbinding factor observed in rat liver (30). This factor, termed IL-6 RE-BP, was induced maximally 4 to 18 h after IL-6 stimulation, and its appearance was shown to depend on ongoing protein synthesis.…”

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confidence: 99%

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Acute-phase response factor, a nuclear factor binding to acute-phase response elements, is rapidly activated by interleukin-6 at the posttranslational level.

Wegenka¹,

Buschmann²,

Lütticken³

et al. 1993

Mol. Cell. Biol.

520

376

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Interleukin-6 (IL-6) is known to be a major mediator of the acute-phase response in liver. We show here that IL-6 triggers the rapid activation of a nuclear factor, termed acute-phase response factor (APRF), both in rat liver in vivo and in human hepatoma (HepG2) cells in vitro. APRF bound to IL-6 response elements in the 5'-flanking regions of various acute-phase protein genes (e.g., the %-macroglobulin, fibrinogen, and al-acid glycoprotein genes). These elements contain a characteristic hexanucleotide motif, CTGGGA, known to be required for the IL-6 responsiveness of these genes. Analysis of the binding specificity of APRF revealed that it is different from NF-IL6 and NF-KB, transcription factors known to be regulated by cytokines and involved in the transcriptional regulation of acute-phase protein genes. In HepG2 cells, activation of APRF was observed within minutes after stimulation with IL-6 or leukemia-inhibitory factor and did not require ongoing protein synthesis. Therefore, a preexisting inactive form of APRF is activated by a posttranslational mechanism. We present evidence that this activation occurs in the cytoplasm and that a phosphorylation is involved. These results lead to the conclusions that APRF is an immediate target of the IL-6 signalling cascade and is likely to play a central role in the transcriptional regulation of many IL-6-induced genes.During an acute inflammation, cytokines released by different cell types, including monocytes, fibroblasts, and endothelial cells, stimulate the synthesis and secretion of a set of plasma proteins, the so-called acute-phase proteins, by the liver. These proteins play a protective role during the acute-phase reaction, e.g., by inactivating proteases, supporting the wound-healing process, or scavenging free oxygen radicals (for a review, see reference 26). According to their regulation by different cytokines, acute-phase proteins have been divided into two subclasses (8). The synthesis of class 1 acute-phase proteins (e.g., a1-acid glycoprotein, C-reactive protein, haptoglobin, and serum amyloid A) is induced by interleukin-1 (IL-1) or combinations of IL-1 and IL-6, whereas the genes for class 2 acute-phase proteins (e.g., a2-macroglobulin, cxl-antichymotrypsin, and fibrinogen) are regulated mainly by IL-6 and glucocorticoids. The 5'-flanking regions of many acute-phase protein genes have been studied in detail, with the goal of identifying regulatory elements required for the cytokine induction of these genes. One type of cytokine response elements found in the promoters of several class 1 acute-phase protein genes represents binding sites for members of the C/EBP family of transcription factors (15,21,49,51,62 (36). In addition, NF-iB or NF-KB-like factors were found to be involved in the regulation of the angiotensinogen, serum amyloid A, and complement factor B genes by 48,54).Less is known about transcription factors regulating the promoters of class 2 acute-phase protein genes. On the basis of a sequence comparison of the 5'-flanking regions of the...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 97%

mentioning

confidence: 98%

mentioning

confidence: 99%

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Acute-phase response factor, a nuclear factor binding to acute-phase response elements, is rapidly activated by interleukin-6 at the posttranslational level.

Wegenka¹,

Buschmann²,

Lütticken³

et al. 1993

Mol. Cell. Biol.

520

376

View full text Add to dashboard Cite

show abstract

“…Transcription factors of the C/EBP family such as human nuclear factor 1L-6 [3], rat IL-6DBP/LAP [4] or mouse AGPEBP [51, now collectively called C/EBP/r 161, and NF-IL-6P also callcd C/EBP6 [7], bind to these elements and are activated by IL-6. A second type of element, L 6 -r esponse elements, is mainly but not exclusively implicated in the regulation of class-2 genes [8]. Its binding-site consensus sequence contains the motif S'TTGGGA which is recognized by factors such as IL-6-response-element-binding protein [8 I and acute-phase response factor signal-transduction activator of transcription (APRFBTAT3) [9] that are also activated by IL-6.…”

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confidence: 99%

Regulation of Expression of the Rat Serine Protease Inhibitor 2.3 Gene by Glucocorticoids and Interleukin‐6

Simar‐Blanchet

Paul

Mercier

et al. 1996

European Journal of Biochemistry

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The rat serine protease inhibitor 2.3 gene (spi 2.3) is almost completely silent in normal animals and is transiently expressed during acute inflammation. It encodes a potential anti-elastase which is likely to play a major physiological role for the host defense. Two well-known inflammatory mediators, glucocorticoids and interleukin-6 (IL-6) activate the spi 2.3 promoter and increase steady-state levels of mRNA in cultured hepatocytes. GC activation is mediated by a single glucocorticoid-response element which seems to act autonomously. A unique array of four functional IL-6-response sites was identified in the spi 2.3 promoter. Three of them (C-IT-1V) bear structural identity to the CCAAT/enhancer-binding-protein-binding site consensus sequence, whereas the forth closely resembles the consensus KB nuclear factor recognition motif. The C-IV element, which is the most active, contains the motif 5'-CTGGGA and binds the IL-6-inducible acute-phase response factor present in liver nuclear extracts from inflamed rats. Both basal and IL-6-dependent activities of each individual cytokine-response element tcsted separately are strongly down regulated by a recently identified regulatory sequence [Le Cam, A. & Legraverend, C. (1995) Eur: J. Biochem. 231, 620-6271, located in the 3' untranslated region of the spi 2.3 gene. However, this repressor element does not significantly affect overall IL-6-dependent spi 2.3 promoter activity. This suggests that, in the context of the active gene in vivo, all four IL-6-response sites, which are largely redundant, cooperate to overcome the strong repressive effect of the 3' untranslated region silencer and are needed to bring about a maximal TL-6 response.These data reveal a novel type of regulation of an acute-phase gene involving different classes of IL-6-response elements controlled by a repressor and acting in conjunction with a glucocorticoid-response element.

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Posttranscriptional regulation of connexin 32 expression in liver during acute inflammation

et al. 1996

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Gap junctions mediate the communication between adjacent cells in tissues. In the liver, connexin 32 (Cx32) subunits make up the predominating gap junctions. The expression of Cx32 gene has been observed to be down-regulated in response to inflammatory states and during liver regeneration. In the present study we attempt to elucidate the molecular mechanisms underlying the down-regulation of the Cx32 expression during acute inflammation. A decrease in the level of Cx32 mRNA in rat liver occurred between 3 and 6 h after intravenous administration of bacterial lipopolysaccharide (LPS), simultaneously with the induction of an acute inflammatory response characterized by an increase in the level for beta-fibrinogen and a reduction of phosphoenolpyruvate carboxykinase mRNA. The reduction in Cx32 steady-state mRNA levels appears to occur at the posttranscriptional level, since the rate of degradation of this message seems to be higher than the rate of transcription of the gene. Degradation of Cx32 mRNA was blocked by the administration of actinomycin D, but not by cycloheximide, prior to injection of LPS. The stabilization of Cx32 message by actinomycin D correlated with the preservation of Cx32 on the cell surface, which otherwise disappears after administration of LPS alone. These results suggest that cellular communication via gap junctions could be regulated at the level of gene expression, by a posttranscriptional mechanism, during acute inflammatory states.

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Transcriptional Control of Liver Acute Phase Genes by Interleukin-6 and Leukemia Inhibitory Factor

Cited by 8 publications

References 11 publications

Acute-phase response factor, a nuclear factor binding to acute-phase response elements, is rapidly activated by interleukin-6 at the posttranslational level.

Acute-phase response factor, a nuclear factor binding to acute-phase response elements, is rapidly activated by interleukin-6 at the posttranslational level.

Regulation of Expression of the Rat Serine Protease Inhibitor 2.3 Gene by Glucocorticoids and Interleukin‐6

Posttranscriptional regulation of connexin 32 expression in liver during acute inflammation

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