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

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.