FOXO3 as a new IKK‐ε‐controlled check‐point of regulation of IFN‐β expression

Cell survival transcription factor FOXO3 has been recently implicated in moderating pro‐inflammatory cytokine production by dendritic cells (DCs), but the molecular mechanisms are unclear. It was suggested that FOXO3 could antagonize NF‐κB activity, while IKK‐β was demonstrated to inactivate FOXO3, suggesting a cross‐talk between the two pathways. Therefore, FOXO3 activity must be tightly regulated to allow for an appropriate inflammatory response. Here, we show that in human monocyte‐derived DCs (MDDCs), FOXO3 is able to antagonize signaling intermediates downstream of the Toll‐like receptor (TLR) 4, such as NF‐κB and interferon regulatory factors (IRFs), resulting in inhibition of interferon (IFN)‐β expression. We also demonstrate that the activity of FOXO3 itself is regulated by IKK‐ε, a kinase involved in IFN‐β production, which phosphorylates and inactivates FOXO3 in response to TLR4 agonists. Thus, we identify FOXO3 as a new IKK‐ε‐controlled check‐point of IRF activation and regulation of IFN‐β expression, providing new insight into the role of FOXO3 in immune response control.