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Ron receptor-dependent gene regulation in a mouse model of endotoxin-induced acute liver failure |
Rishikesh M Kulkarni, Louis W Kutcher, William D Stuart, Daniel J Carson, Mike A Leonis and Susan E Waltz |
Cincinnati, USA
Author Affiliations: Departments of Cancer and Cell Biology (Kulkarni RM, Stuart WD and Waltz SE) and Biology (Kutcher LW and Carson DJ), University of Cincinnati, Cincinnati, OH 45267-0521, USA; Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children s Hospital Medical Center, Cincinnati, OH 45229, USA (Leonis MA); Department of Research, Shriner s Hospital for Children and Cincinnati Veterans Affairs Medical Center, Cincinnati, OH 45267-0521, USA (Waltz SE)
Corresponding Author: Susan E Waltz, PhD, Department of Cancer and Cell Biology, 3125 Eden Ave., University of Cincinnati College of Medicine, Cincinnati, OH 45267-0521, USA (Tel: 513-558-8675; Email: susan.waltz@uc.edu) |
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Abstract BACKGROUND: Prior experimentation has shown that loss of the tyrosine kinase (TK) signaling domain of the Ron receptor leads to marked hepatocyte protection in a model of lipopolysaccharide-induced acute liver failure (ALF) in D-galactosamine (GalN)-sensitized mice. The aim of this study was to identify the role of Ron in the regulation of hepatic gene expression.
METHODS: Microarray analyses were performed on liver RNA isolated sequentially from wild-type (WT) and TK-/- mice during the progression of ALF. Gene array data were validated using Western and immunohistochemistry analyses as well as with ex vivo culture systems.
RESULTS: At baseline, 101 genes were differentially expressed between WT and TK-/- livers, which regulate processes involved in hypoxia, proliferation, apoptosis and metabolism. One hour after ALF induction, WT livers exhibited increased cytokine expression compared to TK-/- livers, and after 4 hours, an induction of suppressor of cytokine signaling (SOCS) genes as well as JAK-STAT pathway activation were prominent in TK-/- livers compared to controls.
CONCLUSION: Our studies suggest a novel hepato-protective mechanism in Ron TK-/- mice wherein increased and sustained SOCS production and JAK-STAT activation in the hepatocyte may inhibit the destructive proinflammatory milieu and promote survival factors which blunt hepatic death and the ensuing development of ALF.
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