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Published on: November 27, 2019
Ron receptor-dependent gene regulation in a mouse model of endotoxin-induced acute liver failure
Rishikesh M Kulkarni1, Louis W Kutcher, William D Stuart
1Departments of Cancer and Cell Biology, University of Cincinnati, Cincinnati, OH 45267-0521, USA.
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.
Insights
Loss of the Ron receptor tyrosine kinase (TK) signaling domain protects liver cells in acute liver failure (ALF). This occurs through sustained suppressor of cytokine signaling (SOCS) production and JAK-STAT activation, reducing inflammation and promoting survival.
Area of Science:
- Hepatology
- Molecular Biology
- Immunology
Background:
- Loss of the Ron receptor tyrosine kinase (TK) signaling domain confers hepatocyte protection in a mouse model of acute liver failure (ALF).
- Understanding Ron's role in hepatic gene expression is crucial for identifying protective mechanisms.
Purpose of the Study:
- To investigate the role of the Ron receptor TK signaling domain in regulating hepatic gene expression during ALF.
- To elucidate the molecular mechanisms underlying Ron-mediated hepatocyte protection.
Main Methods:
- Microarray analysis of liver RNA from wild-type (WT) and TK-/- mice during ALF progression.
- Validation of gene array data using Western blot, immunohistochemistry, and ex vivo cultures.
Main Results:
- Baseline differential expression of 101 genes related to hypoxia, proliferation, apoptosis, and metabolism between WT and TK-/- livers.
- WT livers showed increased cytokine expression post-ALF induction compared to TK-/-.
- TK-/- livers exhibited induced suppressor of cytokine signaling (SOCS) genes and JAK-STAT pathway activation 4 hours after ALF induction.
Conclusions:
- A novel hepatoprotective mechanism involves Ron TK-/- mice exhibiting sustained SOCS production and JAK-STAT activation.
- This sustained signaling likely inhibits the pro-inflammatory milieu, promoting survival factors.
- These mechanisms blunt hepatic death and reduce the development of ALF.
