Deletion of the Ron receptor tyrosine kinase domain in mice provides protection from endotoxin-induced acute liver failure.
The targeted deletion of the cytoplasmic domain of the Ron receptor tyrosine kinase (TK) in mice leads to exaggerated responses to injury in several murine models of inflammation as well as increased lethality in response to endotoxin (lipopolysaccharide [LPS]). Using a well-characterized model of LPS-induced acute liver failure (ALF) in galactosamine (GalN)-sensitized mice, we show that Ron TK(-/-) mice display marked protection compared with control Ron TK(+/+) mice. Whereas control mice have profound elevation of serum aminotransferase levels (a marker of hepatocyte injury) and hemorrhagic necrosis of the liver, in dramatic contrast, Ron TK(-/-) mice have mild elevation of aminotransferase levels and relatively normal liver histology. These findings are associated with a reduction in the number of liver cells undergoing apoptosis in Ron TK(-/-) mice. Paradoxically, treatment of Ron TK(-/-) mice with LPS/GalN leads to markedly elevated (3.5-fold) serum levels of tumor necrosis factor (TNF) alpha, a key inflammatory mediator in this liver injury model, as well as reduced amounts of interleukin (IL) 10 (a suppressor of TNF-alpha production) and interferon (IFN)-gamma (a TNF-alpha sensitizer). These results show that ablation of the TK activity of the Ron receptor leads to protection from the development of hepatocellular apoptosis in response to treatment with LPS/GalN, even in the presence of excessive levels of serum TNF-alpha. In conclusion, our studies show that the Ron receptor TK plays a critical role in modulating the response of the liver to endotoxin.
Leonis
Mike A
MA
Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Research Foundation and Department of Pediatrics, University of Cincinnati, OH 45229, USA.
Toney-Earley
Kenya
K
Degen
Sandra J F
SJ
Waltz
Susan E
SE
D000818:Animals; D017209:Apoptosis; D016207:Cytokines / Q000097:blood; D005688:Galactosamine; D017353:Gene Deletion; D007728:Kupffer Cells / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides; D008099:Liver / Q000201:enzymology / Q000473:pathology; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000201:enzymology* / Q000517:prevention & control*; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry* / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000737:chemistry* / Q000235:genetics*
D016207:Cytokines; D008070:Lipopolysaccharides; D011956:Receptors, Cell Surface; D005688:Galactosamine; D011505:Protein-Tyrosine Kinases; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases