title: FOXO3 as a new IKK-ε-controlled check-point of regulation of IFN-β expression.
abstract: 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.
authors.affiliation: Kennedy Institute of Rheumatology, Imperial College of Science, Technology and Medicine, London, United Kingdom. luron@ciml.univ-mrs.fr
authors.forename: Lionel
authors.initials: L
authors.lastname: Luron
authors.forename: David
authors.initials: D
authors.lastname: Saliba
authors.forename: Katrina
authors.initials: K
authors.lastname: Blazek
authors.forename: Alessandra
authors.initials: A
authors.lastname: Lanfrancotti
authors.forename: Irina A
authors.initials: IA
authors.lastname: Udalova
mesh_terms: D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology*; D057809:HEK293 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016899:Interferon-beta / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D009000:Monocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D016328:NF-kappa B; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D016899:Interferon-beta; D051550:I-kappa B Kinase