Omega 3 polyunsaturated fatty acids modulate cyclooxygenase‐2 induction via interactions with GPR120

Abstract

Cyclooxygenase‐2 (COX‐2)‐derived prostaglandins are implicated in numerous inflammatory disorders. Omega 3 polyunsaturated fatty acids (ω3 PUFAs) such as docosahexaenoic acid (DHA) are recognized as anti‐inflammatory agents. Here, we explore the potential interaction between COX‐2 induction and ω3 PUFAs via the G‐protein‐coupled receptor 120 (GPR120). Pre‐exposure to DHA for 24 h reduced prostaglandin E2 (PGE2) production primarily through COX‐2 inhibition and partially through down‐regulating microsomal prostaglandin E synthase‐1 (mPGES‐1) expression, but not through affecting COX‐1 expression. DHA could also inhibit activation of a human COX‐2 promoter‐luciferase reporter construct containing NF‐κB response elements. We also demonstrated that COX‐2 induction is attenuated in macrophages obtained from Fat‐1 mice where ω3 PUFAs are synthesized endogenously from ω6 PUFAs. In a FeCl3 femoral artery injury mouse model, post‐injury blood flow in Fat‐1 mice was higher relative to their wild type littermates. Knockdown of GPR120 abrogates DHA effects on COX‐2 induction, PGE2 production and interleukin 6 (IL‐6) gene expression, through ERK, Akt, and JNK signaling pathways. These studies provide a new mechanistic basis for the anti‐inflammatory effects of PUFAs via interactions with GPR120. Supported by a joint grant from the CIHR and NSFC (CCI 117951).