2. Academic Validation
  3. Docosahexaenoyl serotonin, an endogenously formed n-3 fatty acid-serotonin conjugate has anti-inflammatory properties by attenuating IL-23-IL-17 signaling in macrophages

Docosahexaenoyl serotonin, an endogenously formed n-3 fatty acid-serotonin conjugate has anti-inflammatory properties by attenuating IL-23-IL-17 signaling in macrophages

  • Biochim Biophys Acta. 2016 Dec;1861(12 Pt A):2020-2028. doi: 10.1016/j.bbalip.2016.09.012.
Mieke Poland 1,  Jean Paul Ten Klooster 2,  Zheng Wang 3,  Raymond Pieters 4,  Mark Boekschoten 5,  Renger Witkamp 6,  Jocelijn Meijerink 7
Affiliations

Affiliations

  • 1 Division of Human Nutrition, Wageningen University, PO Box 17, 6700 AA Wageningen, The Netherlands. Electronic address: [email protected].
  • 2 Institute for Life Sciences & Chemistry, Utrecht University of Applied Sciences, Utrecht, The Netherlands. Electronic address: [email protected].
  • 3 Division of Human Nutrition, Wageningen University, PO Box 17, 6700 AA Wageningen, The Netherlands. Electronic address: [email protected].
  • 4 Institute for Life Sciences & Chemistry, Utrecht University of Applied Sciences, Utrecht, The Netherlands. Electronic address: [email protected].
  • 5 Division of Human Nutrition, Wageningen University, PO Box 17, 6700 AA Wageningen, The Netherlands. Electronic address: [email protected].
  • 6 Division of Human Nutrition, Wageningen University, PO Box 17, 6700 AA Wageningen, The Netherlands. Electronic address: [email protected].
  • 7 Division of Human Nutrition, Wageningen University, PO Box 17, 6700 AA Wageningen, The Netherlands. Electronic address: [email protected].
PMID: 27663185 DOI: 10.1016/j.bbalip.2016.09.012
Abstract

Conjugates of fatty acids and amines, including endocannabinoids, are known to play important roles as endogenous signaling molecules. Among these, the ethanolamine conjugate of the n-3 poly unsaturated long chain fatty acid (PUFA) docosahexaenoic acid (22:6n-3) (DHA) was shown to possess strong anti-inflammatory properties. Previously, we identified the serotonin conjugate of DHA, docosahexaenoyl serotonin (DHA-5-HT), in intestinal tissues and showed that its levels are markedly influenced by intake of n-3 PUFAs. However, its biological roles remain to be elucidated. Here, we show that DHA-5-HT possesses potent anti-inflammatory properties by attenuating the IL-23-IL-17 signaling cascade in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. Transcriptome analysis revealed that DHA-5-HT down-regulates LPS-induced genes, particularly those involved in generating a CD4+ Th17 response. Hence, levels of PGE2, IL-6, IL-1β, and IL-23, all pivotal macrophage-produced mediators driving the activation of pathogenic Th17 cells in a concerted way, were found to be significantly suppressed by concentrations as low as 100-500nM DHA-5-HT. Furthermore, DHA-5-HT inhibited the ability of RAW264.7 cells to migrate and downregulated chemokines like MCP-1, CCL-20, and gene-expression of CCL-22 and of several metalloproteinases. Gene set enrichment analysis (GSEA) suggested negative overlap with gene sets linked to inflammatory bowel disease (IBD) and positive overlap with gene sets related to the Nrf2 pathway. The specific formation of DHA-5-HT in the gut, combined with increasing data underlining the importance of the IL-23-IL-17 signaling pathway in the etiology of many chronic inflammatory diseases merits further investigation into its potential as therapeutic compound in e.g. IBD or intestinal tumorigenesis.

Keywords

Acyl serotonines; DHA; DHA-5-HT; Endocannabinoids; Intestine; Nrf2.

Figures
Products