Department of Medicine III, University Hospital RWTH Aachen, D-52074 Aachen, Germany.
Cell Rep. 2013 Aug 29;4(4):776-90. doi: 10.1016/j.celrep.2013.07.035. Epub 2013 Aug 22.
For years, the term "apoptosis" was used synonymously with programmed cell death. However, it was recently discovered that receptor interacting protein 3 (RIP3)-dependent "necroptosis" represents an alternative programmed cell death pathway activated in many inflamed tissues. Here, we show in a genetic model of chronic hepatic inflammation that activation of RIP3 limits immune responses and compensatory proliferation of liver parenchymal cells (LPC) by inhibiting Caspase-8-dependent activation of Jun-(N)-terminal kinase in LPC and nonparenchymal liver cells. In this way, RIP3 inhibits intrahepatic tumor growth and impedes the Caspase-8-dependent establishment of specific chromosomal aberrations that mediate resistance to tumor-necrosis-factor-induced apoptosis and underlie hepatocarcinogenesis. Moreover, RIP3 promotes the development of jaundice and cholestasis, because its activation suppresses compensatory proliferation of cholangiocytes and hepatic stem cells. These findings demonstrate a function of RIP3 in regulating carcinogenesis and cholestasis. Controlling RIP3 or Caspase-8 might represent a chemopreventive or therapeutic strategy against hepatocellular carcinoma and biliary disease.
多年来，“细胞凋亡”一词一直被用作程序性细胞死亡的同义词。然而，最近发现，受体相互作用蛋白 3（RIP3）依赖性“坏死性凋亡”代表了一种在许多炎症组织中激活的替代程序性细胞死亡途径。在这里，我们在慢性肝炎症的遗传模型中表明，RIP3 的激活通过抑制 Caspase-8 依赖性 LPC 和非实质细胞中 Jun-(N)-末端激酶的激活，限制免疫反应和肝实质细胞（LPC）的代偿性增殖。通过这种方式，RIP3 抑制肝内肿瘤生长，并阻碍 Caspase-8 依赖性建立介导肿瘤坏死因子诱导的凋亡抗性和肝癌发生的特定染色体畸变。此外，RIP3 促进黄疸和胆汁淤积的发展，因为其激活抑制胆管细胞和肝干细胞的代偿性增殖。这些发现表明 RIP3 在调节癌症发生和胆汁淤积方面具有功能。控制 RIP3 或 Caspase-8 可能代表针对肝细胞癌和胆道疾病的化学预防或治疗策略。
