Cytokine-Induced Hepatic Apoptosis Is Dependent on FGL2/Fibroleukin: The Role of Sp1/Sp3 and STAT1/PU.1 CompositecisElements Journal Articles uri icon

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  • AbstractPrevious studies from our laboratory have shown that fulminant hepatitis caused by the mouse hepatitis virus, MHV-3, is dependent on production of the novel immune coagulant fgl2/fibroleukin. In this study, we investigate the role of IFN-γ and TNF-α in the induction of fgl2 expression and fgl2-dependent hepatic apoptosis. Infusion of IFN-γ in combination with TNF-α through the portal vein of fgl2+/+ mice led to widespread hepatic apoptosis and fibrin deposition. Livers from fgl2−/− mice were normal, although strong expression of the fgl2 knockout reporter gene Lac Z was seen in both resident hepatic macrophages and endothelial cells. In vitro, IFN-γ and TNF-α induced fgl2 expression in a macrophage and endothelial cell-specific manner. In macrophages (peritoneal and RAW 264.7 cells), IFN-γ, but not IFN-α, LPS, TNF-α, or IL-1 induced fgl2 mRNA transcription and protein expression, while in endothelial cells TNF-α, but not IFN-γ, induced fgl2 transcription. In addition, while TNF-α enhanced IFN-γ-induced macrophage fgl2 transcription, IFN-γ also enhanced TNF-α-induced endothelial cell fgl2 transcription. The induction of fgl2 by IFN-γ in macrophages involved a STAT1-dependent pathway, involving the composite cis elements Sp1/Sp3 and GAS/PU.1. The latter interacted with IFN-γ-dependent Sp1/Sp3, STAT1, and the ETS family of transcription factors member PU.1. The interaction of PU.1 with the IFN-γ-activated sequence/ETS family of transcription factors site determined the macrophage-specific induction of fgl2 by IFN-γ. Overall, this study demonstrates that IFN-γ and TNF-α induce hepatocyte apoptosis in vivo, which is dependent on induction of fgl2, and defines the molecular basis of transcription of fgl2 in vitro.


  • Liu, Mingfeng
  • Mendicino, Michael
  • Ning, Qin
  • Ghanekar, Anand
  • He, Wei
  • McGilvray, Ian
  • Shalev, Itay
  • Pivato, David
  • Clark, David Alexander
  • Phillips, M James
  • Levy, Gary A

publication date

  • June 1, 2006

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