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

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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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  • Cite this

    Canavan, M., McCarthy, C., Larbi, N. B., Dowling, J. K., Collins, L., O'Sullivan, F., Hurley, G., Murphy, C., Quinlan, A., Moloney, G., Darby, T., MacSharry, J., Kagechika, H., Moynagh, P., Melgar, S., & Loscher, C. E. (2014). Activation of liver X receptor suppresses the production of the IL-12 family of cytokines by blocking nuclear translocation of NF-κBp50. Innate Immunity, 20(7), 675-87. https://doi.org/10.1177/1753425913501915