Differential effects of prostaglandin derived from ω-6 and ω-3 polyunsaturated fatty acids on COX-2 expression and IL-6 secretion

Abstract

Omega-6 (-6) polyunsaturated fatty acids (PUFA), abundant in the Western diet, are precursors for a number of key mediators of inflammation including the 2-series of prostaglandins (PG). PGE 2, a cyclooxygenase (COX) metabolite of arachidonic acid, a -6 PUFA, is a potent mediator of inflammation and cell proliferation. Dietary supplements rich in -3 PUFA reduce the concentrations of 2-series PG and increase the synthesis of 3-series PG (e.g., PGE 3 ), which are believed to be less inflammatory. However, studies on cellular consequences of increases in 3-series PG in comparison to 2-series PG have not been reported. In this study, we compared the effects of PGE 2 and PGE3 on (i) cell proliferation in NIH 3T3 fibroblasts, (ii) expression and transcriptional regulation of the COX-2 gene in NIH 3T3 fibroblasts, and (iii) the production of an inflammatory cytokine, IL-6, in RAW 264.7 macrophages. PGE 3, unlike PGE2, is not mitogenic to NIH 3T3 fibroblasts. PGE 2 and PGE3 both induce COX-2 mRNA via similar signaling mechanisms; however, compared with PGE 2, PGE3 is significantly less efficient in inducing COX-2 gene expression. Furthermore, although both PGE2 and PGE3 induce IL-6 synthesis in RAW 264.7 macrophages, PGE 3 is substantially less efficient compared with PGE2. We further show that increasing the -3 content of membrane phospholipid results in a decrease in mitogen-induced PGE2 synthesis. Taken together, our data suggest that successful replacement of -6 PUFA with -3 PUFA in cell membranes can result in a decreased cellular response to mitogenic and inflammatory stimuli.

Influence of omega-6 PUFA arachidonic acid and bone marrow adipocytes on metastatic spread from prostate cancer

“…The result herein may be because of adipocytes being loaded with EPA in relative isolation to other lipids. Bagga et al (2003) showed that the COX-2 metabolite of EPA, PGE3, although not mitogenic itself, could regulate COX-2 expression and induce IL-6 secretion from macrophages. Although similar in action and signalling to PGE 2 , PGE 3 is not as efficient in inducing COX-2 gene expression.…”

Differential immunomodulation with long-chainn-3 PUFA in health and chronic disease

“…Thus, fish oil supplementation of the human diet has been shown to result in increased production of 5-series LT and 5-hydroxyeicosapentaenoic acid by inflammatory cells (for references, see Calder, 2006). The functional importance of this difference is that the mediators formed from EPA are frequently less potent than those formed from ARA (Goldman et al 1983;Lee et al 1984;Bagga et al 2003), although it is not always the case (Dooper et al 2002;Miles et al 2002Miles et al , 2003. The reduction in generation of ARA-derived mediators that accompanies fish oil consumption has led to the notion that fish oil is anti-inflammatory and immunomodulatory.…”

Epoxy metabolites of docosahexaenoic acid (DHA) inhibit angiogenesis, tumor growth, and metastasis

“…A widely accepted theory to explain the health-promoting effects of omega-3 fatty acids is that they suppress the metabolism of omega-6 arachidonic acid (ARA) to form proangiogenic or proinflammatory eicosanoids or serve as alternative substrates to generate omega-3 lipid mediators with beneficial actions (9). Indeed, the metabolism of omega-3 fatty acids by cyclooxygenase (COX) and lipoxygenase (LOX) enzymes generates 3-series prostaglandins (10,11) and leukotrienes (12), as well as unique omega-3 autacoids such as resolvins and protectins (13), which have antiinflammatory or antiangiogenic effects.…”