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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 lipopolysaccharideinduced 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.
BACKGROUND: Prior experimentation has shown 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 of this study was to identify the role of Ron in the regulation of hepatic gene expression. METHODS: Microarray analyzes 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 as well as with 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. ALF induction, WT livers extracted 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 a ctivation were prominent in TK- / livers compared to controls. CONCLUSION: Our studies suggest suggest a novel hepato-protective mechanism in Ron TK - / - mice were 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.