Activation of NF-κB by IL-1β blocks IL-6-induced sustained STAT3 activation and STAT3-dependent gene expression of the human γ-fibrinogen gene

Ute Albrecht, Xiangping Yang, Rosanna Asselta, Verena Keitel, Maria Luisa Tenchini, Stephan Ludwig, Peter C. Heinrich, Dieter Häussinger, Fred Schaper, Johannes G. Bode

Research output: Contribution to journalArticle

Abstract

Despite the essential role of the fibrinogen γ-chain as a blood clotting factor, the fibrinogen γ-chain contains a number of interaction sites to recruit other factors such as leukocytes important for prevention of pathogen entry and propagation of the repair process. Interleukin-6 (IL-6) is known as the major inducer of γ-fibrinogen synthesis in hepatocytes, whereas IL-1β has been shown to act as a potent inhibitor of γ-fibrinogen expression. Studies on the rat fibrinogen γ-chain promoter suggest that nuclear factor (NF)-κB replaces the signal transducer and activator of transcription (STAT) 3 from binding to overlapping NF-κB/STAT3 binding sites within the 5′ regulatory region of the rat γ-chain gene promoter. However, despite its physiological relevance, the underlying mechanism responsible for the inhibitory effect of IL-1β in humans is still not understood and apparently more complex. In contrast to the mechanism described for the rat gene our results indicate that IL-1β suppresses the IL-6-induced activation of the human γ-fibrinogen gene particularly by blocking the late phase STAT3-tyrosine phosphorylation NF-κB-dependently but independent from de novo protein synthesis. Consequently, blocking NF-κB activation restores specifically late phase STAT3 activation as well as the induction of the human γ-fibrinogen gene. In contrast, specifically early STAT3 activation could be restored by a block of the p38 mitogen-activated protein kinase (p38MAPK) pathway. In summary, our results indicate that expression of the γ-fibrinogen gene is mainly controlled by the strength of late phase STAT3 activation, which in turn is negatively regulated by the extent of IL-1β-mediated NF-κB activity.

Original languageEnglish
Pages (from-to)1866-1878
Number of pages13
JournalCellular Signalling
Volume19
Issue number9
DOIs
Publication statusPublished - Sep 2007

Fingerprint

Interleukin-1
Fibrinogen
Interleukin-6
Gene Expression
Genes
STAT3 Transcription Factor
Blood Coagulation Factors
Nucleic Acid Regulatory Sequences
Blood Coagulation
p38 Mitogen-Activated Protein Kinases
Tyrosine
Hepatocytes
Leukocytes
Binding Sites
Phosphorylation
Proteins

Keywords

  • Acute phase response
  • Cytokines
  • Gene regulation
  • Inflammation
  • Signal transduction
  • Transcription factors

ASJC Scopus subject areas

  • Cell Biology

Cite this

Activation of NF-κB by IL-1β blocks IL-6-induced sustained STAT3 activation and STAT3-dependent gene expression of the human γ-fibrinogen gene. / Albrecht, Ute; Yang, Xiangping; Asselta, Rosanna; Keitel, Verena; Tenchini, Maria Luisa; Ludwig, Stephan; Heinrich, Peter C.; Häussinger, Dieter; Schaper, Fred; Bode, Johannes G.

In: Cellular Signalling, Vol. 19, No. 9, 09.2007, p. 1866-1878.

Research output: Contribution to journalArticle

Albrecht, U, Yang, X, Asselta, R, Keitel, V, Tenchini, ML, Ludwig, S, Heinrich, PC, Häussinger, D, Schaper, F & Bode, JG 2007, 'Activation of NF-κB by IL-1β blocks IL-6-induced sustained STAT3 activation and STAT3-dependent gene expression of the human γ-fibrinogen gene', Cellular Signalling, vol. 19, no. 9, pp. 1866-1878. https://doi.org/10.1016/j.cellsig.2007.04.007
Albrecht, Ute ; Yang, Xiangping ; Asselta, Rosanna ; Keitel, Verena ; Tenchini, Maria Luisa ; Ludwig, Stephan ; Heinrich, Peter C. ; Häussinger, Dieter ; Schaper, Fred ; Bode, Johannes G. / Activation of NF-κB by IL-1β blocks IL-6-induced sustained STAT3 activation and STAT3-dependent gene expression of the human γ-fibrinogen gene. In: Cellular Signalling. 2007 ; Vol. 19, No. 9. pp. 1866-1878.
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abstract = "Despite the essential role of the fibrinogen γ-chain as a blood clotting factor, the fibrinogen γ-chain contains a number of interaction sites to recruit other factors such as leukocytes important for prevention of pathogen entry and propagation of the repair process. Interleukin-6 (IL-6) is known as the major inducer of γ-fibrinogen synthesis in hepatocytes, whereas IL-1β has been shown to act as a potent inhibitor of γ-fibrinogen expression. Studies on the rat fibrinogen γ-chain promoter suggest that nuclear factor (NF)-κB replaces the signal transducer and activator of transcription (STAT) 3 from binding to overlapping NF-κB/STAT3 binding sites within the 5′ regulatory region of the rat γ-chain gene promoter. However, despite its physiological relevance, the underlying mechanism responsible for the inhibitory effect of IL-1β in humans is still not understood and apparently more complex. In contrast to the mechanism described for the rat gene our results indicate that IL-1β suppresses the IL-6-induced activation of the human γ-fibrinogen gene particularly by blocking the late phase STAT3-tyrosine phosphorylation NF-κB-dependently but independent from de novo protein synthesis. Consequently, blocking NF-κB activation restores specifically late phase STAT3 activation as well as the induction of the human γ-fibrinogen gene. In contrast, specifically early STAT3 activation could be restored by a block of the p38 mitogen-activated protein kinase (p38MAPK) pathway. In summary, our results indicate that expression of the γ-fibrinogen gene is mainly controlled by the strength of late phase STAT3 activation, which in turn is negatively regulated by the extent of IL-1β-mediated NF-κB activity.",
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AU - Yang, Xiangping

AU - Asselta, Rosanna

AU - Keitel, Verena

AU - Tenchini, Maria Luisa

AU - Ludwig, Stephan

AU - Heinrich, Peter C.

AU - Häussinger, Dieter

AU - Schaper, Fred

AU - Bode, Johannes G.

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