The role of c-FLIP in the development and activation of dendritic cells
Date Issued
2015
Date
2015
Author(s)
Wu, Yu-Jung
Abstract
The caspase-8-specific inhibitor, cellular FLICE inhibitory protein (c-FLIP), inhibits death receptor-induced apoptosis by blocking caspase-8 activation. c-FLIP has also been reported to transmit activation signals, but the exact signals mediated by c-FLIP remain unclear. The aim of this study is to investigate the role of c-FLIP in the development and activation of dendritic cells (DCs) by using c-FLIPf/fCD11c-Cre (DC-specific) conditional knockout mice. We identified a novel function of c-FLIP involving in inhibition of myeloid cell activation through selective innate signaling pathway. We found that conditional knockout of c-FLIP in dendritic cells led to neutrophilia and splenomegaly. Peripheral dendritic cell populations, including CD11b+ conventional DC (cDC), CD8+ cDC, and plasmacytoid DC (pDC), were not affected by c-FLIP absence. Our results also indicated that c-FLIP-knockout cDC, pDC, and bone marrow-derived DC (BMDC) displayed enhanced production of TNF-a, IL-2, or G-CSF in response to stimulation of TLR4, TLR2, and Dectin-1. Splenic DC maturation and T cell priming ability were also increased in c-FLIPf/fCD11c-Cre mice. Consistent with the ability of c-FLIP to inhibit the activation of p38 MAPK, the enhanced activation of c-FLIP-deficient BMDCs could be partly linked to an increased activation of p38 MAPK after engagement of innate receptors. We showed there was an interaction between c-FLIP and p38 MAPK or c-FLIP and ASK1. In addition, the increased activation in c-FLIP-deficient dendritic cells was caspase-8-independent. Our results reveal a novel inhibitory role of c-FLIP in myeloid cell activation through modulating p38 MAPK signaling and demonstrate the unexpected anti-inflammatory activity of c-FLIP. Moreover, our observations suggest that cancer therapy target c-FLIP downregulation may facilitate DC activation and increase T cell immunity.
Subjects
c-FLIP
dendritic cells
p38 MAPK
SDGs
Type
thesis
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