title: The nuclear receptor LXR modulates interleukin-18 levels in macrophages through multiple mechanisms.
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.
authors.affiliation: Centre for Clinical Pharmacology, Division of Medicine, University College of London, 5 University Street, London, WC1 E6JF, United Kingdom.
authors.forename: Benoit
authors.initials: B
authors.lastname: Pourcet
authors.affiliation: Centre for Clinical Pharmacology, Division of Medicine, University College of London, 5 University Street, London, WC1 E6JF, United Kingdom.
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Gage
authors.affiliation: Centre for Clinical Pharmacology, Division of Medicine, University College of London, 5 University Street, London, WC1 E6JF, United Kingdom.
authors.forename: Theresa E
authors.initials: TE
authors.lastname: León
authors.affiliation: Centre for Clinical Pharmacology, Division of Medicine, University College of London, 5 University Street, London, WC1 E6JF, United Kingdom.
authors.forename: Kirsty E
authors.initials: KE
authors.lastname: Waddington
authors.affiliation: Centre for Clinical Pharmacology, Division of Medicine, University College of London, 5 University Street, London, WC1 E6JF, United Kingdom.
authors.forename: Oscar M
authors.initials: OM
authors.lastname: Pello
authors.affiliation: Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institut, Huddinge, Sweden.
authors.forename: Knut R
authors.initials: KR
authors.lastname: Steffensen
authors.affiliation: Instituto de Investigaciones Biomedicas "Alberto Sols" Consejo Superior de Investigaciones Científicas (CSIC) de Madrid, Unidad de Biomedicina (Unidad Asociada al CSIC), Instituto Universitario de Investigaciones Biomedicas y Sanitarias (IUIBS) de la Universidad de Las Palmas de Gran Canaria, Las Palmas, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Castrillo
authors.affiliation: School of Biology, University of Barcelona, Diagonal 643, Planta 3, 08028 Barcelona, Spain.
authors.forename: Annabel F
authors.initials: AF
authors.lastname: Valledor
authors.affiliation: Centre for Clinical Pharmacology, Division of Medicine, University College of London, 5 University Street, London, WC1 E6JF, United Kingdom.
authors.forename: Inés
authors.initials: I
authors.lastname: Pineda-Torra
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D020382:Interleukin-18 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000276:immunology; D000071518:Liver X Receptors / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000032:analysis
chemical_list: D020382:Interleukin-18; D008070:Lipopolysaccharides; D000071518:Liver X Receptors; D012333:RNA, Messenger