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Cyclooxygenase‐2 induction in macrophages is modulated by docosahexaenoic acid via interactions with free fatty acid receptor 4 (FFA4)
Author(s) -
Li Xinzhi,
Yu Ying,
Funk Colin D.
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.13-235333
Subject(s) - docosahexaenoic acid , gpr120 , cyclooxygenase , eicosanoid , arachidonic acid , chemistry , gene knockdown , lipid signaling , polyunsaturated fatty acid , prostaglandin h2 , receptor , biochemistry , pharmacology , fatty acid , g protein coupled receptor , biology , apoptosis , enzyme
Cyclooxygenase‐2 (COX‐2)‐derived prostaglandins are implicated in numerous inflammatory disorders. The purpose of these studies was to examine previously unexplored interactions between COX‐2 induction and docosahexaenoic acid (DHA) via the free fatty acid receptor 4 (FFA4) signaling pathway in murine RAW 264.7 cells and peritoneal macrophages challenged with lipopolysaccharide (LPS). DHA dose (IC 50 =18 μM)‐ and time‐dependently reduced COX‐2 expression, without affecting COX‐1. DHA (25 μM for 24 h) decreased LPS‐induced prostaglandin E 2 (PGE 2 ) synthesis by 81%, primarily through reducing COX‐2 (60%), as well as down‐regulating microsomal prostaglandin E synthase‐1 (46%), but independently of peroxisome proliferator‐activated receptors. FFA4 knockdown abrogated DHA effects on COX‐2 induction, PGE 2 production, and interleukin 6 (IL‐6) gene expression. In the presence of inhibitors of eicosanoid metabolism via COX‐2, 12/15‐lipoxygenase and CYP450s (rofecoxib (1 μM), PD146176 (2 μM), or MS‐PPOH (20 μM)), DHA was still effective in attenuating COX‐2 induction. Moreover, Toll‐like receptor 4 signaling via Akt/JNK phosphorylation and p65 nuclear translocation was repressed by DHA‐activated FFA4 coupling with β‐arrestin 2, which was reversed by FFA4 knockdown. These data support DHA modulation of COX‐2 expression and activity, in part, via FFA4, which provides a new mechanistic explanation for some of the anti‐inflammatory effects of DHA.—Li, X., Yu, Y., Funk, C. D., Cyclooxygenase‐2 induction in macrophages is modulated by docosahexaenoic acid via interactions with free fatty acid receptor 4 (FFA4). FASEB J. 27, 4987–4997 (2013). www.fasebj.org