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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)
Nuclear receptors (Biochemistry)
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.
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It is part of: Scientific Reports, 2016, vol. 6, p. 25481
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ISSN: 2045-2322
Appears in Collections:Articles publicats en revistes (Biologia Cel·lular, Fisiologia i Immunologia)

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