title: 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.
abstract: 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.
authors.affiliation: Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Yueqin
authors.initials: Y
authors.lastname: Liu
authors.forename: Li-Yuan
authors.initials: LY
authors.lastname: Chen
authors.forename: Milena
authors.initials: M
authors.lastname: Sokolowska
authors.forename: Michael
authors.initials: M
authors.lastname: Eberlein
authors.forename: Sara
authors.initials: S
authors.lastname: Alsaaty
authors.forename: Asuncion
authors.initials: A
authors.lastname: Martinez-Anton
authors.forename: Carolea
authors.initials: C
authors.lastname: Logun
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Qi
authors.forename: James H
authors.initials: JH
authors.lastname: Shelhamer
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D015232:Dinoprostone / Q000096:biosynthesis*; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005395:Fish Oils / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008744:Methylamines / Q000494:pharmacology; D051379:Mice; D054467:Phospholipases A2 / Q000378:metabolism*; D011422:Propionates / Q000494:pharmacology; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000378:metabolism; D014162:Transfection
chemical_list: C519853:FFAR4 protein, human; D005395:Fish Oils; C515630:GW9508; D008744:Methylamines; D011422:Propionates; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; D058309:Receptors, Prostaglandin E, EP4 Subtype; D004281:Docosahexaenoic Acids; D054467:Phospholipases A2; D015232:Dinoprostone
keywords: cytokines; inflammation; lipid mediators; signal transduction