Ron receptor-dependent gene regulation in a mouse model of endotoxin-induced acute liver failure.
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.


CONCLUSIONS
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.
Departments of Cancer and Cell Biology, University of Cincinnati, Cincinnati, OH 45267-0521, USA.
Rishikesh M
RM
Kulkarni
Louis W
LW
Kutcher
William D
WD
Stuart
Daniel J
DJ
Carson
Mike A
MA
Leonis
Susan E
SE
Waltz
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005688:Galactosamine; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D007150:Immunohistochemistry; D018836:Inflammation Mediators / Q000378:metabolism; D053612:Janus Kinases / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides; D008099:Liver / Q000201:enzymology* / Q000473:pathology; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D020794:Receptor Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050791:STAT Transcription Factors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D050791:STAT Transcription Factors; D050826:Suppressor of Cytokine Signaling Proteins; D005688:Galactosamine; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases; D053612:Janus Kinases