Omega-3 fatty acids cause dramatic changes in TLR4 and purinergic eicosanoid signaling

Abstract

Dietary fish oil omega‐3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), elicit cardioprotective and anti‐inflammatory effects through unresolved mechanisms. EPA and DHA may reduce arachidonic acid (AA) metabolism and pro‐inflammatory effects by competition and inhibition at multiple levels. Here, we report the effects of AA, EPA, and DHA supplementation on membrane incorporation, phospholipase A2 release, and eicosanoid production in RAW264.7 macrophages. Each PUFA supplemented increased by similar amounts in membrane phospholipids, while half of the increased AA and EPA were elongated to adrenic acid (AdA) and docosapentaenoic acid (DPA), respectively; and were subsequently released by PLA2 at levels comparable to AA. TLR‐4 stimulated COX‐2 AA production did not increase with AA supplementation and was inhibited by 20% and 50% after EPA and DHA supplementation, respectively. ATP stimulated COX‐1 AA production was inhibited to a greater extent by EPA and DHA; 5‐LOX AA metabolites increased 2‐fold with EPA and DHA supplementation, and 5‐LOX metabolized EPA and DHA to a greater extent than COX‐1/COX‐2. Altogether, AA, EPA and DHA supplementation decreased TLR‐4 stimulated AA COX‐2 prostanoid metabolism; increased the purinergic stimulated AA 5‐LOX/COX‐1 ratio; and significantly increased elongated PUFA levels that may be converted to novel mediators.

Pulmonary epithelial cancer cells and their exosomes metabolize myeloid cell-derived leukotriene C4 to leukotriene D4

“…This was found both in early work (20) and in recent lipidomic analyses (21)(22)(23)(24). Likewise, eosinophils (25)(26)(27) and mast cells (28)(29)(30)(31)(32) produce mainly LTC 4 , but apparently no or only small amounts of LTD 4 .…”

“…Monocytic cells (macrophages, dendritic cells), mast cells, and eosinophils are fundamental previous studies on human blood monocytes and human peritoneal macrophages using incubation times up to 60 min [see (20) and references therein]. Also, in more recent lipidomic analyses of mouse peritoneal macrophages (21) and RAW264.7 murine macrophages (22,23), LTC 4 and 5-HETE (but not LTD 4 ) were major 5-LO products. In a recent study of macrophages, FACS-sorted from a mouse lung tumors, LTC 4 was more than 10-fold more abundant than LTD 4 (24).…”

Docosapentaenoic Acid (22:5n-3) Downregulates mRNA Expression of Pro-inflammatory Factors in LPS-activated Murine Macrophage Like RAW264.7 Cells

“…Weldon et al reported that DHA exhibits greater anti-inflammatory effect on human THP-1 macrophages as compared to that of EPA 25 . Norris and Dennis reported that EPA indirectly inhibits COX through elongation to n-3 DPA 26 . However, no information regarding the ability of n-3 DPA to regulate mRNA expression of pro-inflammatory factors in activated macrophages was described.…”

GM‐CSF– and M‐CSF–primed macrophages present similar resolving but distinct inflammatory lipid mediator signatures

“…Depending on the expression and activation of eicosanoid-forming enzymes and their proximity to cPLA 2 , cells may preferentially shunt AA toward one of these pathways (6). Lipidomic analysis has been applied to study AA metabolism in mouse peritoneal Mfs (9), RAW264.7 Mfs (10,11), mouse mast cells (12), and Mfs from mouse lung tumors (13). Lipid mediators released from fully activated M1 and M2 human Mfs have also been determined (14).…”