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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.

Original publication

DOI

10.1002/eji.201141969

Type

Journal article

Journal

Eur J Immunol

Publication Date

04/2012

Volume

42

Pages

1030 - 1037

Keywords

Dendritic Cells, Forkhead Box Protein O3, Forkhead Transcription Factors, Gene Expression Regulation, HEK293 Cells, Humans, I-kappa B Kinase, Interferon-beta, Monocytes, NF-kappa B, Phosphorylation, Signal Transduction, Toll-Like Receptor 4