E2F1 Suppreses DC Maturation (88.22)

Abstract

Abstract E2F1 has been largely studied as a promoter of cell cycle and as regulator of apoptosis. Recently, E2F1 has been shown to regulate a wide range of genes in response to inflammatory stimulation of macrophages and to contribute to T cell activation in response to pathogens, implicating an extensive immunological role for E2F1. Dendritic cells (DCs) play critical roles as professional antigen-presenting cells in the development of immune responses, however, it is unclear whether E2F1 has any effect on DC phenotype and function. Here, we report that E2F1 acts as a suppressor of DC maturation. The level of E2F1 expression was transiently downregulated in the course of LPS-induced maturation of both human monocyte-derived dendritic cells and a mouse DC cell line, DC2.4. Knockdown of E2F1 by siRNA in DC2.4 cells resulted in both phenotypic and functional maturation, even without LPS treatment. Conversely, ectopic overexpression of E2F1 suppressed LPS-induced maturation of DC2.4 cells. Furthermore, knockdown of E2F1 caused the activation of several major signaling pathways known to be activated in the course of DC maturation, including Erk1/2, NF-κB and PI3K/Akt, suggesting that E2F1 may be involved in regulating multiple signaling pathways in DCs. Finally, the alternation by E2F1 on phenotypic maturation was confirmed with bone marrow-derived DCs from E2F1-KO mice. Overall, our data demonstrate for the first time that E2F1 is a critical regulator of dendritic cell maturation.