Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

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

European journal of immunology

Publication Date

04/2012

Volume

42

Pages

1030 - 1037

Addresses

Kennedy Institute of Rheumatology, Imperial College of Science, Technology and Medicine, London, United Kingdom. luron@ciml.univ-mrs.fr

Keywords

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