Necroptosis facilitates cell death in a controlled manner and is employed by many cell types following injury. It plays a major role in various liver diseases, albeit the cell type-specific regulation of necroptosis in the liver and especially hepatocytes has not yet been conceptualized. Here, we demonstrate that DNA methylation suppresses RIPK3 expression in human hepatocytes and HepG2 cells. In diseases leading to cholestasis the RIPK3 expression is induced in mice and humans in a cell-type specific manner. Over-expression of RIPK3 in HepG2 cells leads immediately to RIPK3 activation by phosphorylation that is further modulated by different bile acids. Bile acids mediated RIPK3 activation facilitates the secretion and expression of IL-8 via the JNK-pathway, suggesting hepatocytes suppress RIPK3 expression to protect themselves from bile acid induced necroptosis and inflammation but in chronical liver diseases associated with cholestasis induction of RIPK3 expression may be an early event signaling danger and repair through release of IL-8.

中文翻译：

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肝细胞中RIPK3启动子的高度甲基化可防止胆汁酸引起的炎症和坏死

坏死病以受控的方式促进细胞死亡，并且在损伤后被许多细胞类型所利用。它在各种肝脏疾病中起着重要作用，尽管还没有概念化对肝特别是肝细胞中坏死病的细胞类型进行特异性调节。在这里，我们证明DNA甲基化抑制人肝细胞和HepG2细胞中RIPK3的表达。在导致胆汁淤积的疾病中，RIPK3表达以细胞类型特异性方式在小鼠和人类中被诱导。RIPK3在HepG2细胞中的过表达会立即导致RIPK3的磷酸化激活，而磷酸化又被不同的胆汁酸调节。胆汁酸介导的RIPK3激活通过JNK途径促进IL-8的分泌和表达，