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Cytokine-Induced Hepatic Apoptosis Is Dependent on FGL2/Fibroleukin: The Role of Sp1/Sp3 and STAT1/PU.1 Composite cis Elements

Mingfeng Liu^*, Michael Mendicino^*, Qin Ning, Anand Ghanekar^*, Wei He^*, Ian McGilvray^*, Itay Shalev^*, David Pivato^*, David A. Clark^*, M. James Phillips^* and Gary A. Levy^1,*

^* Multi-Organ Transplant Program, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada; and Department of Infectious Disease, Tongji Hospital, Medical College, Wuhan, China

Previous 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- and TNF- in the induction of fgl2 expression and fgl2-dependent hepatic apoptosis. Infusion of IFN- in combination with TNF- 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- and TNF- induced fgl2 expression in a macrophage and endothelial cell-specific manner. In macrophages (peritoneal and RAW 264.7 cells), IFN-, but not IFN-, LPS, TNF-, or IL-1 induced fgl2 mRNA transcription and protein expression, while in endothelial cells TNF-, but not IFN-, induced fgl2 transcription. In addition, while TNF- enhanced IFN--induced macrophage fgl2 transcription, IFN- also enhanced TNF--induced endothelial cell fgl2 transcription. The induction of fgl2 by IFN- in macrophages involved a STAT1-dependent pathway, involving the composite cis elements Sp1/Sp3 and GAS/PU.1. The latter interacted with IFN--dependent Sp1/Sp3, STAT1, and the ETS family of transcription factors member PU.1. The interaction of PU.1 with the IFN--activated sequence/ETS family of transcription factors site determined the macrophage-specific induction of fgl2 by IFN-. Overall, this study demonstrates that IFN- and TNF- induce hepatocyte apoptosis in vivo, which is dependent on induction of fgl2, and defines the molecular basis of transcription of fgl2 in vitro.

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