Omega-3 fatty acid (FA) emulsions reduce LPS-stimulated murine macrophage TNF-alpha production, but the exact mechanism has yet to be defined. The purpose of this study was to determine the mechanism for omega-3 FA inhibition of macrophage TNF-alpha production following LPS stimulation. RAW 264.7 cells were pretreated with isocaloric emulsions of omega-3 FA (Omegaven), omega-6 FA (Lipovenos), or DMEM and subsequently exposed to LPS. IkappaB-alpha and phospho-IkappaB-alpha were determined by Western blotting. NF-kappaB binding was assessed using the electromobility shift assay, and activity was measured using a luciferase reporter vector. RT-PCR and ELISA quantified TNF-alpha mRNA and protein levels, respectively. Pretreatment with omega-3 FA inhibited IkappaB phosphorylation and significantly decreased NF-kappaB activity. Moreover, omega-3-treated cells demonstrated significant decreases in both TNF-alpha mRNA and protein expression by 47 and 46%, respectively. These experiments demonstrate that a mechanism for proinflammatory cytokine inhibition in murine macrophages by omega-3 FA is mediated, in part, through inactivation of the NF-kappaB signal transduction pathway secondary to inhibition of IkappaB phosphorylation.

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Four-hour omega-3 FA emulsion pretreatment significantly attenuated LPS-stimulated macrophage TNF-alpha production. These data support the contention that antiinflammatory effects of omega-3 FA occur at least in part through the inhibition of macrophage TNF-alpha production in response to endotoxin. Further studies to define the antiinflammatory mechanisms of omega-3 FA on macrophages are warranted. The availability of Omegaven as an experimental treatment and Lipovenos as an equivalent control will be useful for future studies.

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Background-Omega-3 FA (ω-3 FA) have been demonstrated to have anti-inflammatory properties; postulated to occur through several principal mechanisms, including 1) displacement of arachidonic acid from the cellular membrane, 2) shifting of PGE 2 and LTB 4 production and 3) molecular level alterations including decreased activation of NF-κB and AP-1. An additional regulator that is likely associated is the production of nitric oxide (NO) by nitric oxide synthetase. NO is a short-lived free radical involved in many biological functions. However, excessive NO production can lead to complications, suggesting that decreased NO production is a potential target for some inflammatory diseases. We hypothesized that pretreating with an ω-3 FA lipid emulsion would decrease the production of NO in macrophages and that this effect would occur through alterations in inducible nitric oxide synthetase (iNOS).