Key Points
Polyunsaturated fats can be metabolized to a large family of bioactive lipid mediators known as oxylipins. The best studied oxylipins are those derived from the omega-6 fatty acid arachidonic acid (AA), also called eicosanoids. Oxylipins can be produced from other PUFAs as well, including omega-6 fatty acids linoleic acid (LA) and dihomo-γ-linolenic acid (DGLA) and omega-3 fatty acids ALA, EPA and DHA. The anti-inflammatory effects of ALA have traditionally been attributed to the bioconversion of ALA to longer-chain EPA and DHA before production
of oxylipins. The fact that the conversion rate is quite low, as well as the fact that several ALA oxylipins can be detected in blood and tissues at relatively high concentrations has led some to question whether effects of ALA oxylipins themselves and/or effects on oxylipins derived from precursors other than EPA and DHA also contribute to the overall anti-inflammatory phenotype induced by ALA. The objective of this study was to determine if treatment with ALA can dampen the inflammatory properties of THP-1-derived M1-like macrophages, a model for the cell population found pathogenically elevated in inflamed tissue such as obese adipose tissue, and to examine the accompanying effects on oxylipin production. It was shown that exposure to ALA concurrently with classical activation stimulation suppresses the M1 phenotype without enhancing production of DHA oxylipins while increasing ALA and LOX-derived LA oxylipins. ALA present during classical activation can substantially dampen the proinflammatory phenotype of M1-like macrophages. ALA and LA oxylipins are prominently induced in this context and likely contribute to the overall cytokine-lowering effect, while the results suggest little contribution by EPA oxylipins and no contribution by DHA oxylipins. This highlights the urgent need to characterize the functions of ALA oxylipins and lesser-known LA oxylipins in various cell types since they hold promise as anti-inflammatory agents. The results obtained
here using this cell culture model support the appealing suggestion that increased ALA in the adipose tissue environment of obese humans, achievable by increasing dietary intake, might dampen the inflammatory phenotype of developing M1 macrophages and thus protect against secondary complications of obesity-associated inflammation or other chronic inflammatory conditions.
ABSTRACT
Chronic inflammation, mediated in large part by proinflammatory macrophage populations, contributes directly to the induction and perpetuation of metabolic diseases, including obesity, insulin resistance and type 2 diabetes. Polyunsaturated fatty acids (PUFAs) can have profound effects on inflammation through the formation of bioactive oxygenated metabolites called oxylipins. The objective of this study was to determine if exposure to the dietary omega-3 PUFA α-linolenic acid (ALA) can dampen the inflammatory properties of classically activated (M1-like) macrophages derived from the human THP-1 cell line and to examine the accompanying alterations in oxylipin secretion. We find that ALA treatment leads to a reduction in lipopolysaccharide (LPS)-induced interleukin (IL)-1β, IL-6 and tumor necrosis factor-α production. Although ALA is known to be converted to longer-chain PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), DHA oxylipins were reduced overall by ALA treatment, as was LPS-induced secretion of EPA oxylipins. In contrast, we observed profound increases in oxylipins directly derived from ALA. Lipoxygenase products of linoleic acid were also dramatically increased, and LPS-induced production of AA oxylipins, particularly prostaglandin D2, was reduced. These results suggest that ALA may act to dampen the inflammatory phenotype of M1-like macrophages by a unique set of mechanisms distinct from those used by the long-chain omega-3 fatty acids EPA and DHA. Thus, there is strong rationale for investigating the functions of ALA oxylipins and lesser-known LA oxylipins since they hold promise as anti-inflammatory agents.
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