| Summary: | 博士 === 國防醫學院 === 生命科學研究所 === 92 === FADD and caspase-8-mediated apoptotic signals initiated by death receptor engagement. Recent studies reveal that FADD and caspase-8 are also indispensable for T cell activation. c-FLIP is a specific inhibitor for death receptor-induced apoptosis by interaction with FADD and procaspase-8. c-FLIP was shown to activate ERK and enhance IL-2 production. It is suggested that c-FLIP transmits activated signals, and the failure to recruit c-FLIP in the absence of FADD and caspase-8 results in defective in T cell activation.
In order to delineate the exact role of c-FLIP in T cell activation, c-FLIP was expressed in different T cell lines by retroviral infection in the present study. The expression of c-FLIP was confirmed by specific inhibition of Fas-mediated apoptosis. We found that IL-2 production of c-FLIP-expressing DO11.10 T cells was inhibited, in contrast to the increase in IL-2 production in Jurkat cells overexpressing c-FLIP. We determined the activation signals in DO11.10 and Jurkat cells with or without c-FLIP expression. c-FLIP transduction inhibited p38 MAPK activation and Ca2+ influx in DO11.10 cells, yet enhanced ERK activation in Jurkat cells. ERK activity was normal in c-FLIP-DO11.10, while p38 MAPK activation and Ca2+ influx were unaffected in c-FLIP-Jurkat cells. The inhibitory activity of c-FLIP seems to be distinct from the stimulatory activity of c-FLIP. Human T leukemia cell lines such as Jurkat are characteristic for their absence of PTEN and constitutive activation of PI 3-kinase. We examined whether constitutive PI 3-K contributed to the stimulatory activity of c-FLIP in Jurkat cells. Inhibition of PI 3-K with Wortmannin and LY294002 abrogated c-FLIP-mediated IL-2 production increase in Jurkat cells. Coexpression of c-FLIP and active form PI 3-K enhanced the activity of ERK. Reintroducing PTEN into Jurkat cells eliminated c-FLIP-mediated increase of ERK activation and IL-2 production. Our results suggest that c-FLIP by itself does not activate T cells, the stimulatory activity of c-FLIP on T cell activation could be detected only through coordination of with PI 3-K.
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