title: Activation of liver X receptor suppresses the production of the IL-12 family of cytokines by blocking nuclear translocation of NF-κBp50.
abstract: There is now convincing evidence that liver X receptor (LXR) is an important modulator of the inflammatory response; however, its mechanism of action remains unclear. This study aimed to examine the effect of LXR on the IL-12 family of cytokines and examined the mechanism by which LXR exerted this effect. We first demonstrated that activation of murine-derived dendritic cells (DC) with a specific agonist to LXR enhanced expression of LXR following activation with LPS, suggesting a role in inflammation. Furthermore, we showed LXR expression to be increased in vivo in dextrane sulphate sodium-induced colitis. LXR activation also suppressed production of IL-12p40, IL-12p70, IL-27 and IL-23 in murine-derived DC following stimulation with LPS, and specifically targeted the p35, p40 and EBI3 subunits of the IL-12 cytokine family, which are under the control of the NF-κB subunit p50 (NF-κBp50). Finally, we demonstrated that LXR can associate with NF-κBp50 in DC and that LXR activation prevents translocation of the p50 subunit into the nucleus. In summary, our study indicates that LXR can specifically suppress the IL-12 family of cytokines though its association with NF-κBp50 and highlights its potential as a therapeutic target for chronic inflammatory diseases.
authors.affiliation: Immunomodulation Research Group, School of Biotechnology, Dublin City University, Dublin, Ireland.
authors.forename: Mary
authors.initials: M
authors.lastname: Canavan
authors.affiliation: Immunomodulation Research Group, School of Biotechnology, Dublin City University, Dublin, Ireland.
authors.forename: Ciara
authors.initials: C
authors.lastname: McCarthy
authors.affiliation: Immunomodulation Research Group, School of Biotechnology, Dublin City University, Dublin, Ireland.
authors.forename: Nadia Ben
authors.initials: NB
authors.lastname: Larbi
authors.affiliation: Immunomodulation Research Group, School of Biotechnology, Dublin City University, Dublin, Ireland.
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Dowling
authors.affiliation: Immunomodulation Research Group, School of Biotechnology, Dublin City University, Dublin, Ireland.
authors.forename: Laura
authors.initials: L
authors.lastname: Collins
authors.affiliation: National Institute for Cellular Biotechnology, Dublin City University, Dublin, Ireland.
authors.forename: Finbarr
authors.initials: F
authors.lastname: O'Sullivan
authors.affiliation: Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.
authors.forename: Grainne
authors.initials: G
authors.lastname: Hurley
authors.affiliation: Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.
authors.forename: Carola
authors.initials: C
authors.lastname: Murphy
authors.affiliation: Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.
authors.forename: Aoife
authors.initials: A
authors.lastname: Quinlan
authors.affiliation: Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.
authors.forename: Gerry
authors.initials: G
authors.lastname: Moloney
authors.affiliation: Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.
authors.forename: Trevor
authors.initials: T
authors.lastname: Darby
authors.affiliation: Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.
authors.forename: John
authors.initials: J
authors.lastname: MacSharry
authors.affiliation: Institute of Biomaterials & Bioengineering, Tokyo Medical & Dental University, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kagechika
authors.affiliation: Institute of Immunology, National University of Ireland, Maynooth, Ireland.
authors.forename: Paul
authors.initials: P
authors.lastname: Moynagh
authors.affiliation: Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland.
authors.forename: Silvia
authors.initials: S
authors.lastname: Melgar
authors.affiliation: Immunomodulation Research Group, School of Biotechnology, Dublin City University, Dublin, Ireland christine.loscher@dcu.ie.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Loscher
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects / Q000276:immunology; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D003593:Cytoplasm / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D018664:Interleukin-12 / Q000096:biosynthesis*; D000071518:Liver X Receptors; D051379:Mice; D008807:Mice, Inbred BALB C; D052002:NF-kappa B p50 Subunit / Q000037:antagonists & inhibitors*; D057093:Orphan Nuclear Receptors / Q000187:drug effects*; D021381:Protein Transport; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics
chemical_list: D016207:Cytokines; D000071518:Liver X Receptors; D052002:NF-kappa B p50 Subunit; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D018664:Interleukin-12
keywords: Liver X receptor; NF-κB; dendritic cells; interleukin-12