The fish oil ingredient, docosahexaenoic acid, activates cytosolic phospholipase A₂ via GPR120 receptor to produce prostaglandin E₂ and plays an anti-inflammatory role in macrophages

Immunology. 2014 Sep;143(1):81-95. doi: 10.1111/imm.12296.


Docosahexaenoic acid (DHA) is one of the major ingredients of fish oil and has been reported to have anti-inflammatory properties mediated through the GPR120 receptor. Whether cytosolic phospholipase A2 (cPLA2 ) and lipid mediators produced from cPLA2 activation are involved in the anti-inflammatory role of DHA in macrophages has not been reported. We report here that DHA and the GPR120 agonist, GW9508, activate cPLA2 and cyclooxygenase 2 (COX-2), and cause prostaglandin E2 (PGE2) release in a murine macrophage cell line RAW264.7 and in human primary monocyte-derived macrophages. DHA and GW9508 activate cPLA2 via GPR120 receptor, G protein Gαq and scaffold protein β-arrestin 2. Extracellular signal-regulated kinase 1/2 activation is involved in DHA- and GW9508-induced cPLA2 activation, but not p38 mitogen-activated protein kinase. The anti-inflammatory role of DHA and GW9508 is in part via activation of cPLA2 , COX-2 and production of PGE2 as a cPLA2 inhibitor or a COX-2 inhibitor partially reverses the DHA- and GW9508-induced inhibition of lipopolysaccharide-induced interleukin-6 secretion. The cPLA2 product arachidonic acid and PGE2 also play an anti-inflammatory role. This effect of PGE2 is partially through inhibition of the nuclear factor-κB signalling pathway and through the EP4 receptor of PGE2 because an EP4 inhibitor or knock-down of EP4 partially reverses DHA inhibition of lipopolysaccharide-induced interleukin-6 secretion. Hence, DHA has an anti-inflammatory effect partially through induction of PGE2.

Keywords: cytokines; inflammation; lipid mediators; signal transduction.

MeSH terms

  • Animals
  • Blotting, Western
  • Cell Line
  • Cytoplasm / drug effects
  • Cytoplasm / metabolism
  • Dinoprostone / biosynthesis*
  • Docosahexaenoic Acids / pharmacology*
  • Enzyme Activation / drug effects
  • Enzyme-Linked Immunosorbent Assay
  • Fish Oils / pharmacology
  • Humans
  • Inflammation / metabolism
  • Macrophages / drug effects*
  • Macrophages / metabolism
  • Methylamines / pharmacology
  • Mice
  • Phospholipases A2 / metabolism*
  • Propionates / pharmacology
  • RNA, Small Interfering
  • Real-Time Polymerase Chain Reaction
  • Receptors, G-Protein-Coupled / metabolism*
  • Receptors, Prostaglandin E, EP4 Subtype / metabolism
  • Transfection


  • FFAR4 protein, human
  • Fish Oils
  • GW9508
  • Methylamines
  • Propionates
  • RNA, Small Interfering
  • Receptors, G-Protein-Coupled
  • Receptors, Prostaglandin E, EP4 Subtype
  • Docosahexaenoic Acids
  • Phospholipases A2
  • Dinoprostone