Uncontrolled
inflammation is an underlying etiology for multiple diseases and macrophages orchestrate
inflammation largely through the production of oxidized
fatty acids known as oxylipids. Previous studies showed that
selenium (Se) status altered the expression of oxylipids and magnitude of inflammatory responses. Although
selenoproteins are thought to mediate many of the
biological effects of Se, the direct effect of
selenoproteins on the production of oxylipids is unknown. Therefore, the role of decreased
selenoprotein activity in modulating the production of biologically active oxylipids from macrophages was investigated. Thioglycollate-elicited peritoneal macrophages were collected from wild-type and myeloid-cell-specific
selenoprotein knockout mice to analyze oxylipid production by liquid chromatography/mass spectrometry as well as oxylipid biosynthetic
enzyme and inflammatory marker gene expression by quantitative real-time polymerase chain reaction. Decreased
selenoprotein activity resulted in the accumulation of
reactive oxygen species, enhanced
cyclooxygenase and
lipoxygenase expression and decreased oxylipids with known anti-inflammatory properties such as
arachidonic acid-derived
lipoxin A₄ (LXA₄) and
linoleic acid-derived 9-oxo-octadecadienoic
acid (9-oxoODE). Treating RAW 264.7 macrophages with LXA₄ or 9-oxoODE diminished
oxidant-induced macrophage inflammatory response as indicated by decreased production of TNFα. The results show for the first time that
selenoproteins are important for the balanced biosynthesis of pro- and anti-inflammatory oxylipids during
inflammation. A better understanding of the Se-dependent control mechanisms governing oxylipid biosynthesis may uncover nutritional intervention strategies to counteract the harmful effects of uncontrolled
inflammation due to oxylipids.