The caspase-8 inhibitor FLIP promotes activation of NF-kappa B and Erk signaling pathways

Background: Activation of Fas (CD95) by its ligand (FasL) rapidly induces c ell death through recruitment and activation of caspase-8 via the adaptor p rotein Fas-associated death domain protein (FADD). However, Fas signals do not always result in apoptosis but can also trigger a pathway that leads to proliferation. We investigated the level at which the two conflicting Fas signals diverge and the protein(s) that are implicated in switching the res ponse. Results: Under conditions in which proliferation of CD3-activated human T l ymphocytes is increased by recombinant Fast, there was activation of the tr anscription factors NF-kappa B and AP-1 and recruitment of the caspase-8 in hibitor and FADD-interacting protein FLIP (FLICE-like inhibitory protein). Fas-recruited FLIP interacts with TNF-receptor associated factors 1 and 2, as well as with the kinases RIP and Raf-1, resulting in the activation of t he NF-kappa B and extracellular signal regulated kinase (Erk) signaling pat hways. in T cells these two signal pathways are critical for interleukin-2 production. Increased expression of FLIP in T cells resulted in increased p roduction of interleukin-2. Conclusions: We provide evidence that FLIP is not simply an inhibitor of de ath-receptor-induced apoptosis but that it also mediates the activation of NF-kappa B and Erk by virtue of its capacity to recruit adaptor proteins in volved in these signaling pathways.