Activation of NF-kappaB by IL-1beta blocks IL-6-induced sustained STAT3 activation and STAT3-dependent gene expression of the human gamma-fibrinogen gene


Despite the essential role of the fibrinogen gamma-chain as a blood clotting factor, the fibrinogen gamma-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 gamma-fibrinogen synthesis in hepatocytes, whereas IL-1beta has been shown to act as a potent inhibitor of gamma-fibrinogen expression. Studies on the rat fibrinogen gamma-chain promoter suggest that nuclear factor (NF)-kappaB replaces the signal transducer and activator of transcription (STAT) 3 from binding to overlapping NF-kappaB/STAT3 binding sites within the 5' regulatory region of the rat gamma-chain gene promoter. However, despite its physiological relevance, the underlying mechanism responsible for the inhibitory effect of IL-1beta 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-1beta suppresses the IL-6-induced activation of the human gamma-fibrinogen gene particularly by blocking the late phase STAT3-tyrosine phosphorylation NF-kappaB-dependently but independent from de novo protein synthesis. Consequently, blocking NF-kappaB activation restores specifically late phase STAT3 activation as well as the induction of the human gamma-fibrinogen gene. In contrast, specifically early STAT3 activation could be restored by a block of the p38 mitogen-activated protein kinase (p38(MAPK)) pathway. In summary, our results indicate that expression of the gamma-fibrinogen gene is mainly controlled by the strength of late phase STAT3 activation, which in turn is negatively regulated by the extent of IL-1beta-mediated NF-kappaB activity.


Projects: A1.3: Identification of crucial metabolic processes during hepatocyte pr..., A2.2: Regulation of pro-apoptotic and anti-apoptotic responses in hepato..., A2.4: Linking signalling pathways regulating liver regeneration and orga..., A3.2: Cross-talk of signaling pathways and endocytic machinery in hepato...

Cell. Signal.
Cell. Signal. 19(9): 1866-78
1st May 2007

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

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[Ute Albrecht] [Dieter Häussinger] [Johannes Bode]

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Views: 2161
  • Created: 31st Aug 2012 at 11:47
  • Last updated: 24th Oct 2013 at 16:23

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