ORCID Profile
0000-0001-9523-0586
Current Organisations
University of Oxford
,
University of Malta
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Publisher: Springer Science and Business Media LLC
Date: 2011
Publisher: Wiley
Date: 04-2012
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.
Publisher: American Society of Hematology
Date: 03-06-2010
DOI: 10.1182/BLOOD-2010-01-263020
Abstract: Spatially and temporally controlled expression of inflammatory mediators is critical for an appropriate immune response. In this study, we define the role for interferon regulatory factor 5 (IRF5) in secretion of tumor necrosis factor (TNF) by human dendritic cells (DCs). We demonstrate that DCs but not macrophages have high levels of IRF5 protein, and that IRF5 is responsible for the late-phase expression of TNF, which is absent in macrophages. Sustained TNF secretion is essential for robust T-cell activation by DCs. Systematic bioinformatic and biochemical analyses of the TNF gene locus map 2 sites of IRF5 recruitment: 5′ upstream and 3′ downstream of the TNF gene. Remarkably, while IRF5 can directly bind to DNA in the upstream region, its recruitment to the downstream region depends on the protein-protein interactions with NF-κB RelA. This study provides new insights into erse molecular mechanisms employed by IRF5 to regulate gene expression and implicates RelA-IRF5 interactions as a putative target for cell-specific modulation of TNF expression.
Publisher: Elsevier BV
Date: 04-2013
Publisher: Proceedings of the National Academy of Sciences
Date: 17-08-2015
Abstract: Many of the world’s major chronic diseases are driven by inflammation. The most abundant inflammatory cells in these diseases are myeloid cells, such as macrophages and neutrophils. Both cell types show remarkable phenotypic ersity among tissues. Defining molecular factors that control this ersity provides abundant scope for the generation of more specific and effective therapeutics, as the lack of specificity of the current most widely used antiinflammatory approaches, such as glucocorticoids and nonsteroidal antiinflammatory molecules, leads to widespread problems if used long term, even at relatively low doses. In this study we demonstrate that a transcription factor called IFN regulatory factor 5 controls macrophage and neutrophil aspects of inflammation, and thus its blockade might be an effective therapeutic strategy for multiple indications.
Publisher: Elsevier BV
Date: 09-2014
Publisher: Springer Science and Business Media LLC
Date: 07-2017
DOI: 10.1038/NATURE23013
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for David Saliba.