The anti‐inflammatory compound palmitoylethanolamide inhibits prostaglandin and hydroxyeicosatetraenoic acid production by a macrophage cell line

The anti‐inflammatory agent palmitoylethanolamide (PEA) reduces cyclooxygenase (COX) activity in vivo in a model of inflammatory pain. It is not known whether the compound reduces prostaglandin production in RAW264.7 cells, whether such an action is affected by compounds preventing the breakdown of endogenous PEA, whether other oxylipins are affected, or whether PEA produces direct effects upon the COX‐2 enzyme. RAW264.7 cells were treated with lipopolysaccharide and interferon‐γ to induce COX‐2. At the level of mRNA, COX‐2 was induced >1000‐fold following 24 h of the treatment. Coincubation with PEA (10 μmol/L) did not affect the levels of COX‐2, but reduced the levels of prostaglandins D(2) and E(2) as well as 11‐ and 15‐hydroxyeicosatetraenoic acid, which can also be synthesised by a COX‐2 pathway in macrophages. These effects were retained when hydrolysis of PEA to palmitic acid was blocked. Linoleic acid‐derived oxylipin levels were not affected by PEA. No direct effects of PEA upon the oxygenation of either arachidonic acid or 2‐arachidonoylglycerol by COX‐2 were found. It is concluded that in lipopolysaccharide and interferon‐γ‐stimulated RAW264.7 cells, PEA reduces the production of COX‐2‐derived oxylipins in a manner that is retained when its metabolism to palmitic acid is inhibited.