Modeling the TNFα-induced apoptosis pathway in hepatocytes.
Modeling the TNFα-induced apoptosis pathway in hepatocytes.
复制标题
DOI：
10.1371/journal.pone.0018646
复制
发表时间：
2011-04-20
期刊：
影响因子：
3.7
通讯作者：
Merfort I
中科院分区：
文献类型：
--
作者：
Schlatter R;Schmich K;Lutz A;Trefzger J;Sawodny O;Ederer M;Merfort I
促炎细胞因子TNFα不能引起离体肝细胞的细胞死亡，但在与慢性炎症相关的肝脏疾病中与肝细胞凋亡有关。最近，我们发现TNFα能够使胶原上培养的原代小鼠肝细胞对Fas配体诱导的凋亡敏感，并提出了增敏效应的数学模型。在这里，我们分析了TNFα如何与转录抑制剂放线菌素D（ActD）联合诱导细胞凋亡。TNFR激活后活性氧簇（ROS）的积累对JNK的持续激活至关重要，JNK的持续激活随后触发线粒体途径依赖性凋亡。此外，JNK的量以ROS依赖性方式强烈上调。与TNFα +放线菌酮相比，未观察到cFLIP降解，表明存在不同的细胞凋亡途径，其中不涉及瘙痒介导的cFLIP降解和主要的caspase-8活化。获得各自的促凋亡因子和抗凋亡因子的时间分辨数据，并进行数学建模。在这些数据的基础上，我们开发了一个数学模型，再现了复杂的相互作用，调节磷酸化状态的JNK和ROS的产生。该模型与我们的TNFα/Fas配体致敏模型以及已发表的NF-κ B模型完全整合。由此产生的综合模型提供了TNFα和FasL途径，NF-κB和ROS之间的动态相互作用的洞察力，并给出了一个成功的模型集成的例子。
The proinflammatory cytokine TNFα fails to provoke cell death in isolated hepatocytes but has been implicated in hepatocyte apoptosis during liver diseases associated with chronic inflammation. Recently, we showed that TNFα is able to sensitize primary murine hepatocytes cultured on collagen to Fas ligand-induced apoptosis and presented a mathematical model of the sensitizing effect. Here, we analyze how TNFα induces apoptosis in combination with the transcriptional inhibitor actinomycin D (ActD). Accumulation of reactive oxygen species (ROS) in response to TNFR activation turns out to be critical for sustained activation of JNK which then triggers mitochondrial pathway-dependent apoptosis. In addition, the amount of JNK is strongly upregulated in a ROS-dependent way. In contrast to TNFα plus cycloheximide no cFLIP degradation is observed suggesting a different apoptosis pathway in which the Itch-mediated cFLIP degradation and predominantly caspase-8 activation is not involved. Time-resolved data of the respective pro- and antiapoptotic factors are obtained and subjected to mathematical modeling. On the basis of these data we developed a mathematical model which reproduces the complex interplay regulating the phosphorylation status of JNK and generation of ROS. This model was fully integrated with our model of TNFα/Fas ligand sensitizing as well as with a published NF-κB-model. The resulting comprehensive model delivers insight in the dynamical interplay between the TNFα and FasL pathways, NF-κB and ROS and gives an example for successful model integration.
登录
查看更多内容
影响因子：
9.8
作者：
Albeck JG;Burke JM;Spencer SL;Lauffenburger DA;Sorger PK
通讯作者：
Sorger PK
影响因子：
9.9
作者：
Cheong, Raymond;Hoffmann, Alexander;Levchenko, Andre
通讯作者：
Levchenko, Andre
影响因子：
--
作者：
Harrington, Heather A.;Ho, Kenneth L.;Tung, K. C.
通讯作者：
Tung, K. C.
影响因子：
11.4
作者：
Chang, DW;Xing, Z;Yang, XL
通讯作者：
Yang, XL
影响因子：
46.9
作者：
Fussenegger, M;Bailey, JE;Varner, J
通讯作者：
Varner, J