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http://hdl.handle.net/2445/116575
Title: | The nuclear receptor lxr modulates interleukin-18 levels in macrophages through multiple mechanisms |
Author: | Pourcet, Benoit Gage, Matthew C. León Moreno, Theresa Elizabeth Waddington, Kirsty E. Pello, Oscar M. Steffensen, Knut R. Castrillo, Antonio Valledor Fernández, Annabel Pineda-Torra, Inés |
Keywords: | Receptors nuclears (Bioquímica) Macròfags Nuclear receptors (Biochemistry) Macrophages |
Issue Date: | 6-May-2016 |
Publisher: | Nature Publishing Group |
Abstract: | IL-18 is a member of the IL-1 family involved in innate immunity and inflammation. Deregulated levels of IL-18 are involved in the pathogenesis of multiple disorders including inflammatory and metabolic diseases, yet relatively little is known regarding its regulation. Liver X receptors or LXRs are key modulators of macrophage cholesterol homeostasis and immune responses. Here we show that LXR ligands negatively regulate LPS-induced mRNA and protein expression of IL-18 in bone marrow-derived macrophages. Consistent with this being an LXR-mediated process, inhibition is abolished in the presence of a specific LXR antagonist and in LXR-deficient macrophages. Additionally, IL-18 processing of its precursor inactive form to its bioactive state is inhibited by LXR through negative regulation of both pro-caspase 1 expression and activation. Finally, LXR ligands further modulate IL-18 levels by inducing the expression of IL-18BP, a potent endogenous inhibitor of IL-18. This regulation occurs via the transcription factor IRF8, thus identifying IL-18BP as a novel LXR and IRF8 target gene. In conclusion, LXR activation inhibits IL-18 production through regulation of its transcription and maturation into an active pro-inflammatory cytokine. This novel regulation of IL-18 by LXR could be applied to modulate the severity of IL-18 driven metabolic and inflammatory disorders. |
Note: | Reproducció del document publicat a: https://doi.org/10.1038/srep25481 |
It is part of: | Scientific Reports, 2016, vol. 6, p. 25481 |
URI: | http://hdl.handle.net/2445/116575 |
Related resource: | https://doi.org/10.1038/srep25481 |
ISSN: | 2045-2322 |
Appears in Collections: | Articles publicats en revistes (Biologia Cel·lular, Fisiologia i Immunologia) |
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