Regulation by dietary essential fatty acid balance of tumor necrosis factor production in mouse macrophages

Increasing the dietary α-linolenate (18:3n-3)/linoleate (18:2n-6) ratio results in an increase in lipopolysaccharide (LPS)-stimulated tumor necrosis factor (TNF) production in mouse resident and casein-induced peritoneal macrophages. We found that prostaglandin E₂ (PGE₂) production is inversely related to TNF production and that indomethacin abolishes the effect of changing the essential fatty acid balance in resident macrophages. The resident macrophages enriched in n-3 did not produce a significant amount of PGE₃. Accordingly, the decreased production of PGE₂ appears to be a major negative regulatory factor for enhancement of TNF production in the n-3 enriched resident macrophages. In casein-induced macrophages the situation is more complex. Indomethacin decreased PGE₂ production and increased TNF production; however, the differences in TNF production between the n-6 enriched and n-3 enriched macrophages were not completely abolished by indomethacin treatment. Lysosomal acid phosphatase activity, a marker of activation/maturation stages, was elevated in the n-3 enriched compared to the n-6 enriched casein-induced macrophages but was similar in the resident macrophages of the two dietary groups. Expression of CD14, which is a receptor for LPS, was not different in casein-induced macrophages of the two dietary groups. Thus, the differences in production of TNF between the n-3 and n-6 enriched resident macrophages can be accounted for mostly by a difference in the production of a negative feedback effector, PGE₂. However, a significant portion of the TNF production in casein-induced macrophages is regulated by a factor(s) other than PGE₂ and LPS receptor; advanced activation/maturation stages induced by the diet high in α-linolenate may underlie the enhanced TNF production in casein-induced macrophages.