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

Mieke Poland, Jean Paul ten Klooster, Zheng Wang, Raymond Pieters, Mark Boekschoten, Renger Witkamp, Jocelijn Meijerink

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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 100–500 nM 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.

LanguageEnglish
Pages2020-2028
JournalBiochimica et Biophysica Acta. Molecular and Cell Biology of Lipids
Volume1861
Issue number12
DOIs
Publication statusPublished - 2016

Fingerprint

Interleukin-23
Interleukin-17
Omega-3 Fatty Acids
Serotonin
Anti-Inflammatory Agents
Macrophages
Inflammatory Bowel Diseases
Genes
Lipopolysaccharides
Fatty Acids
Down-Regulation
Th17 Cells
Endocannabinoids
Ethanolamine
Docosahexaenoic Acids
Metalloproteases
Gene Expression Profiling
Chemokines
Dinoprostone
Amines

Keywords

  • Acyl serotonines
  • DHA
  • DHA-5-HT
  • Endocannabinoids
  • Intestine
  • Nrf2

Cite this

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title = "Docosahexaenoyl serotonin, an endogenously formed n-3 fatty acid-serotonin conjugate has anti-inflammatory properties by attenuating IL-23–IL-17 signaling in macrophages",
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 100–500 nM 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",
author = "Mieke Poland and {ten Klooster}, {Jean Paul} and Zheng Wang and Raymond Pieters and Mark Boekschoten and Renger Witkamp and Jocelijn Meijerink",
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journal = "Biochimica et Biophysica Acta. Molecular and Cell Biology of Lipids",
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TY - JOUR

T1 - Docosahexaenoyl serotonin, an endogenously formed n-3 fatty acid-serotonin conjugate has anti-inflammatory properties by attenuating IL-23–IL-17 signaling in macrophages

AU - Poland, Mieke

AU - ten Klooster, Jean Paul

AU - Wang, Zheng

AU - Pieters, Raymond

AU - Boekschoten, Mark

AU - Witkamp, Renger

AU - Meijerink, Jocelijn

PY - 2016

Y1 - 2016

N2 - 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 100–500 nM 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.

AB - 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 100–500 nM 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.

KW - Acyl serotonines

KW - DHA

KW - DHA-5-HT

KW - Endocannabinoids

KW - Intestine

KW - Nrf2

U2 - 10.1016/j.bbalip.2016.09.012

DO - 10.1016/j.bbalip.2016.09.012

M3 - Article

VL - 1861

SP - 2020

EP - 2028

JO - Biochimica et Biophysica Acta. Molecular and Cell Biology of Lipids

T2 - Biochimica et Biophysica Acta. Molecular and Cell Biology of Lipids

JF - Biochimica et Biophysica Acta. Molecular and Cell Biology of Lipids

SN - 1388-1981

IS - 12

ER -