| Summary: | 碩士 === 臺灣大學 === 藥理學研究所 === 95 === Fas is the prototype of the death receptors which can directly activate caspases and eventually lead to apoptosis in various cell types. The molecular mechanism of Fas-mediated apoptosis has been well investigated. However, besides apoptosis, recent studies showed that Fas can induce some non-apoptotic signaling pathways under conditions where apoptosis pathways have been inhibited. Nowadays, the molecular mechanism of these alternative signaling pathways mediated by Fas remains unclear. In this study, we investigated the signaling pathway of Fas-mediated caspase-independent cell death and the coupling of this alternative cell death to inflammatory responses in mouse embryonic fibroblasts (MEFs). We found that in MEFs, FasL induced cell death was sensitized under pre-treatment of pan-caspase inhibitor z-VAD-FMK. Our results revealed that RIP and TRAF2 may play important roles in FasL-induced caspase-independent cell death. This death is also associated with intracellular reactive oxygen species (ROS) accumulation, as the ROS scavenger butylated hydroxyanisol (BHA) can prevent the cell death. Furthermore, delayed and sustained JNK, NF-kB activation, and mitochondrial membrane potential breakdown were observed. These phenomena can be eliminated by pre-treatment of BHA. We also found that in company with caspase-independent cell death, Fas ligand can also induce strong inflammatory responses including COX-2 and IL-8 gene up-regulation. This inflammatory response is associated with the delayed and sustained JNK and NF-kB activation. Taken together, we demonstrate caspase-independent signaling pathway of Fas in MEF, and show its activation lead to cell death and inflammatory responses.
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