title: 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.
abstract: 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.
authors.affiliation: Clinic for Gastroenterology, Hepatology and Infectiology, Heinrich-Heine-University, 40255 Düsseldorf, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Albrecht
authors.forename: Xiangping
authors.initials: X
authors.lastname: Yang
authors.forename: Rosanna
authors.initials: R
authors.lastname: Asselta
authors.forename: Verena
authors.initials: V
authors.lastname: Keitel
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Tenchini
authors.forename: Stephan
authors.initials: S
authors.lastname: Ludwig
authors.forename: Peter C
authors.initials: PC
authors.lastname: Heinrich
authors.forename: Dieter
authors.initials: D
authors.lastname: Häussinger
authors.forename: Fred
authors.initials: F
authors.lastname: Schaper
authors.forename: Johannes G
authors.initials: JG
authors.lastname: Bode
mesh_terms: D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D004789:Enzyme Activation / Q000187:drug effects; D005340:Fibrinogen / Q000037:antagonists & inhibitors / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D053583:Interleukin-1beta / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology*; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism*; D051381:Rats; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D015850:Interleukin-6; D016328:NF-kappa B; C106644:SOCS3 protein, human; D050796:STAT3 Transcription Factor; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C027539:fibrinopeptides gamma; D005340:Fibrinogen; D051550:I-kappa B Kinase; D048051:p38 Mitogen-Activated Protein Kinases