The nuclear receptor lxr modulates interleukin-18 levels in macrophages through multiple mechanisms

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...

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Autores: 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
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2016
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/116575
Acceso en línea:https://hdl.handle.net/2445/116575
Access Level:acceso abierto
Palabra clave:Receptors nuclears (Bioquímica)
Macròfags
Nuclear receptors (Biochemistry)
Macrophages
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spelling The nuclear receptor lxr modulates interleukin-18 levels in macrophages through multiple mechanismsPourcet, BenoitGage, Matthew C.León Moreno, Theresa ElizabethWaddington, Kirsty E.Pello, Oscar M.Steffensen, Knut R.Castrillo, AntonioValledor Fernández, AnnabelPineda-Torra, InésReceptors nuclears (Bioquímica)MacròfagsNuclear receptors (Biochemistry)MacrophagesIL-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.Nature Publishing Group2016info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/116575Articles publicats en revistes (Biologia Cel·lular, Fisiologia i Immunologia)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1038/srep25481Scientific Reports, 2016, vol. 6, p. 25481https://doi.org/10.1038/srep25481cc-by (c) Pourcet et al., 2016http://creativecommons.org/licenses/by/3.0/esinfo:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1165752026-05-27T06:46:51Z
dc.title.none.fl_str_mv The nuclear receptor lxr modulates interleukin-18 levels in macrophages through multiple mechanisms
title The nuclear receptor lxr modulates interleukin-18 levels in macrophages through multiple mechanisms
spellingShingle The nuclear receptor lxr modulates interleukin-18 levels in macrophages through multiple mechanisms
Pourcet, Benoit
Receptors nuclears (Bioquímica)
Macròfags
Nuclear receptors (Biochemistry)
Macrophages
title_short The nuclear receptor lxr modulates interleukin-18 levels in macrophages through multiple mechanisms
title_full The nuclear receptor lxr modulates interleukin-18 levels in macrophages through multiple mechanisms
title_fullStr The nuclear receptor lxr modulates interleukin-18 levels in macrophages through multiple mechanisms
title_full_unstemmed The nuclear receptor lxr modulates interleukin-18 levels in macrophages through multiple mechanisms
title_sort The nuclear receptor lxr modulates interleukin-18 levels in macrophages through multiple mechanisms
dc.creator.none.fl_str_mv 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
author Pourcet, Benoit
author_facet 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
author_role author
author2 Gage, Matthew C.
León Moreno, Theresa Elizabeth
Waddington, Kirsty E.
Pello, Oscar M.
Steffensen, Knut R.
Castrillo, Antonio
Valledor Fernández, Annabel
Pineda-Torra, Inés
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Receptors nuclears (Bioquímica)
Macròfags
Nuclear receptors (Biochemistry)
Macrophages
topic Receptors nuclears (Bioquímica)
Macròfags
Nuclear receptors (Biochemistry)
Macrophages
description 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.
publishDate 2016
dc.date.none.fl_str_mv 2016
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/116575
url https://hdl.handle.net/2445/116575
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1038/srep25481
Scientific Reports, 2016, vol. 6, p. 25481
https://doi.org/10.1038/srep25481
dc.rights.none.fl_str_mv cc-by (c) Pourcet et al., 2016
http://creativecommons.org/licenses/by/3.0/es
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Pourcet et al., 2016
http://creativecommons.org/licenses/by/3.0/es
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv Articles publicats en revistes (Biologia Cel·lular, Fisiologia i Immunologia)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,300719

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