Format

Send to

Choose Destination
FASEB J. 2013 Dec;27(12):4987-97. doi: 10.1096/fj.13-235333. Epub 2013 Sep 4.

Cyclooxygenase-2 induction in macrophages is modulated by docosahexaenoic acid via interactions with free fatty acid receptor 4 (FFA4).

Author information

1
1Department of Biomedical and Molecular Sciences, Queen's University, Botterell Hall, Rm. 433, 18 Stuart St., Kingston, ON, Canada, K7L 3N6. funkc@queensu.ca.

Abstract

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 (IC50=18 μM)- and time-dependently reduced COX-2 expression, without affecting COX-1. DHA (25 μM for 24 h) decreased LPS-induced prostaglandin E2 (PGE2) 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, PGE2 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.

KEYWORDS:

GPR120; inflammation; prostaglandin; ω3 polyunsaturated fatty acids

PMID:
24005906
DOI:
10.1096/fj.13-235333
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Atypon
Loading ...
Support Center