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: Mary Canavan, Ciara McCarthy, Nadia Ben Larbi, Jennifer K Dowling, Laura Collins, Finbarr O'Sullivan, Grainne Hurley, Carola Murphy, Aoife Quinlan, Gerry Moloney, Trevor Darby, John MacSharry, Hiroyuki Kagechika, Paul Moynagh, Silvia Melgar, Christine E Loscher
• Journal: Innate immunity (Innate Immun) Vol. 20 Issue 7 Pg. 675-87 (Oct 2014) ISSN: 1753-4267 [Electronic] United States
• PMID: 24045337 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Chemical References

• Cytokines
• Liver X Receptors
• NF-kappa B p50 Subunit
• Orphan Nuclear Receptors
• RNA, Messenger
• Interleukin-12

Topics

• Animals
• Bone Marrow Cells (drug effects, immunology)
• Cell Nucleus (metabolism, pathology)
• Colitis (chemically induced, metabolism)
• Cytokines (biosynthesis)
• Cytoplasm (metabolism, pathology)
• Inflammation (metabolism, pathology)
• Interleukin-12 (biosynthesis)
• Liver X Receptors
• Mice
• Mice, Inbred BALB C
• NF-kappa B p50 Subunit (antagonists & inhibitors)
• Orphan Nuclear Receptors (drug effects)
• Protein Transport
• RNA, Messenger (biosynthesis, genetics)