title: Ron receptor regulates Kupffer cell-dependent cytokine production and hepatocyte survival following endotoxin exposure in mice.
abstract: Previous studies demonstrated that targeted deletion of the Ron receptor tyrosine kinase (TK) domain in mice leads to marked hepatocyte protection in a well-characterized model of lipopolysaccharide (LPS)-induced acute liver failure in D-galactosamine (GalN)-sensitized mice. Hepatocyte protection in TK-/- mice was observed despite paradoxically elevated serum levels of tumor necrosis factor alpha (TNF-α). To understand the role of Ron in the liver, purified populations of Kupffer cells and hepatocytes from wildtype (TK+/+) and TK-/- mice were studied. Utilizing quantitative reverse-transcription polymerase chain reaction (RT-PCR), we demonstrated that Ron is expressed in these cell types. Moreover, we also recapitulated the protected hepatocyte phenotype and exaggerated cytokine production observed in the TK-/- mice in vivo through the use of purified cultured cells ex vivo. We show that isolated TK-/- Kupffer cells produce increased levels of TNF-α and select cytokines compared to TK+/+ cells following LPS stimulation. We also show that conditioned media from LPS-treated TK-/- Kupffer cells was more toxic to hepatocytes than control media, suggesting the exaggerated levels of cytokines produced from the TK-/- Kupffer cells are detrimental to wildtype hepatocytes. In addition, we observed that TK-/- hepatocytes were more resistant to cell death compared to TK+/+ hepatocytes, suggesting that Ron functions in both the epithelial and inflammatory cell compartments to regulate acute liver injury. These findings were confirmed in vivo in mice with hepatocyte and macrophage cell-type-specific conditional Ron deletions. Mice with Ron loss selectively in hepatocytes exhibited less liver damage and increased survival compared to mice with Ron loss in macrophages.
  
  
  CONCLUSIONS
  We dissected cell-type-specific roles for Ron such that this receptor modulates cytokine production from Kupffer cells and inhibits hepatocyte survival in response to injury.
authors.affiliation: Department of Cancer and Cell Biology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: William D
authors.initials: WD
authors.lastname: Stuart
authors.forename: Rishikesh M
authors.initials: RM
authors.lastname: Kulkarni
authors.forename: Jerilyn K
authors.initials: JK
authors.lastname: Gray
authors.forename: Juozas
authors.initials: J
authors.lastname: Vasiliauskas
authors.forename: Mike A
authors.initials: MA
authors.lastname: Leonis
authors.forename: Susan E
authors.initials: SE
authors.lastname: Waltz
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004731:Endotoxins / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects* / Q000502:physiology; D007728:Kupffer Cells / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology*
chemical_list: D004731:Endotoxins; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases