Departments of Cancer and Cell Biology, University of Cincinnati, Cincinnati, OH 45267-0521, USA.
Hepatobiliary Pancreat Dis Int. 2012 Aug 15;11(4):383-92. doi: 10.1016/s1499-3872(12)60196-9.
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.
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.
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.
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.
先前的实验表明，Ron 受体的酪氨酸激酶 (TK) 信号域缺失会导致半乳糖胺 (GalN) 敏化小鼠脂多糖诱导的急性肝衰竭 (ALF) 模型中肝保护作用显著。本研究的目的是确定 Ron 在调节肝基因表达中的作用。
在 ALF 进展过程中，对来自野生型 (WT) 和 TK-/- 小鼠的肝 RNA 进行微阵列分析。使用 Western 和免疫组织化学分析以及离体培养系统验证基因芯片数据。
在基线时，WT 和 TK-/- 肝脏之间有 101 个基因表达差异，这些基因调节与缺氧、增殖、凋亡和代谢有关的过程。ALF 诱导后 1 小时，与 TK-/- 肝脏相比，WT 肝脏的细胞因子表达增加，4 小时后，与对照相比，TK-/- 肝脏中 SOCS 基因的诱导以及 JAK-STAT 途径的激活更为明显。
我们的研究表明 Ron TK-/- 小鼠中存在一种新的肝保护机制，其中肝细胞中 SOCS 产生增加和持续激活以及 JAK-STAT 激活可能抑制破坏性的促炎环境，并促进存活因子，从而阻止肝死亡和随后发生的 ALF。
