Activation of liver X receptor suppresses the production of the IL-12 family of cytokines by blocking nuclear translocation of NF-κBp50

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

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)
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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.

Original languageEnglish
Pages (from-to)675-87
JournalInnate Immunity
Volume20
Issue number7
DOIs
Publication statusPublished - 01 Oct 2014

Keywords

  • Animals
  • Bone Marrow Cells
  • Cell Nucleus
  • Colitis
  • Cytokines
  • Cytoplasm
  • Inflammation
  • Interleukin-12
  • Liver X Receptors
  • Mice
  • Mice, Inbred BALB C
  • NF-kappa B p50 Subunit
  • Orphan Nuclear Receptors
  • Protein Transport
  • RNA, Messenger
  • Journal Article
  • Research Support, Non-U.S. Gov't

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