The fish oil ingredient, docosahexaenoic acid, activates cytosolic phospholipase A 2 via GPR120 receptor to produce prostaglandin E 2 and plays an anti‐inflammatory role in macrophages

Summary 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 A 2 ( cPLA 2 ) and lipid mediators produced from cPLA 2 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 cPLA 2 and cyclooxygenase 2 (COX‐2), and cause prostaglandin E 2 (PGE 2 ) release in a murine macrophage cell line RAW264.7 and in human primary monocyte‐derived macrophages. DHA and GW9508 activate cPLA 2 via GPR120 receptor, G protein G α q and scaffold protein β ‐arrestin 2. Extracellular signal‐regulated kinase 1/2 activation is involved in DHA‐ and GW9508‐induced cPLA 2 activation, but not p38 mitogen‐activated protein kinase. The anti‐inflammatory role of DHA and GW9508 is in part via activation of cPLA 2 , COX‐2 and production of PGE 2 as a cPLA 2 inhibitor or a COX‐2 inhibitor partially reverses the DHA‐ and GW9508‐induced inhibition of lipopolysaccharide‐induced interleukin‐6 secretion. The cPLA 2 product arachidonic acid and PGE 2 also play an anti‐inflammatory role. This effect of PGE 2 is partially through inhibition of the nuclear factor‐κB signalling pathway and through the EP4 receptor of PGE 2 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 PGE 2 .