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

被引:48
作者
Albrecht, Ute
Yang, Xiangping
Asselta, Rosanna
Keitel, Verena
Tenchini, Maria Luisa
Ludwig, Stephan
Heinrich, Peter C.
Haeussinger, Dieter
Schaper, Fred
Bode, Johannes G.
机构
[1] Univ Dusseldorf, Dept Gastroenterol Hepatol & Infectiol, Clin Gastroenterol Hepatol & Infectiol, D-40225 Dusseldorf, Germany
[2] Univ Munster, Dept Mol Virol, D-48149 Munster, Germany
[3] Univ Aachen, Rhein Westfal TH Aachen, Sch Med, Dept Biochem, D-52074 Aachen, Germany
[4] Univ Milan, Dept Biol & Genet Med Sci, I-20133 Milan, Italy
关键词
acute phase response; signal transduction; transcription factors; gene regulation; inflammation; cytokines;
D O I
10.1016/j.cellsig.2007.04.007
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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-1 beta 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)-kappa B replaces the signal transducer and activator of transcription (STAT) 3 from binding to overlapping NF-kappa B/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-1 beta 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-1 beta suppresses the IL-6-induced activation of the human gamma-fibrinogen gene particularly by blocking the late phase STAT3-tyrosine phosphorylation NF-kappa B-dependently but independent from de novo protein synthesis. Consequently, blocking NF-kappa B 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-1 beta-mediated NF-kappa B activity. (c) 2007 Elsevier Inc. All rights reserved.
引用
收藏
页码:1866 / 1878
页数:13
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