Polyunsaturated Fatty Acid-derived lipid mediators and T cell function.

The endogenous cellular and molecular mechanisms that control acute inflammation and its resolution are of wide interest. Using self-resolving inflammatory exudates and lipidomics, we have identified a new pathway involving biosynthesis of potent antiinflammatory and proresolving mediators from the essential fatty acid docosahexaenoic acid (DHA) by macrophages (MΦs). During the resolution of mouse peritonitis, exudates accumulated both 17-hydroxydocosahexaenoic acid, a known marker of 17S-D series resolvin (Rv) and protectin biosynthesis, and 14S-hydroxydocosa-4Z,7Z,10Z,12E,16Z,19Z-hexaenoic acid from endogenous DHA. Addition of either DHA or 14S-hydroperoxydocosa-4Z,7Z,10Z,12E,16Z,19Z-hexaenoic acid to activated MΦs converted these substrates to novel dihydroxy-containing products that possessed potent antiinflammatory and proresolving activity with a potency similar to resolvin E1, 5S,12R,18R-trihydroxyeicosa-6Z,8E,10E,14Z,16E-pentaenoic acid, and protectin D1, 10R,17S-dihydroxydocosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid. Stable isotope incorporation, intermediate trapping, and characterization of physical and biological properties of the products demonstrated a novel 14-lipoxygenase pathway, generating bioactive 7,14-dihydroxydocosa-4Z,8,10,12,16Z,19Z-hexaenoic acid, coined MΦ mediator in resolving inflammation (maresin), which enhances resolution. These findings suggest that maresins and this new metabolome may be involved in some of the beneficial actions of DHA and MΦs in tissue homeostasis, inflammation resolution, wound healing, and host defense.

The n-6 fatty acid arachidonic acid (AA; 20:4n-6) gives rise to eicosanoid mediators that have established roles in inflammation and AA metabolism is a long recognised target for commonly used anti-inflammatory therapies. It has generally been assumed that all AA-derived eicosanoids are pro-inflammatory. However this is an over-simplification since some actions of eicosanoids are anti-inflammatory (e.g. prostaglandin (PG) E(2) inhibits production of some inflammatory cytokines) and it has been discovered quite recently that PGE(2) inhibits production of inflammatory leukotrienes and induces production of inflammation resolving lipoxin A(4). The n-3 fatty acids from oily fish and "fish oils", eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3), are incorporated into inflammatory cell phospholipids in a time- and dose-dependent manner. They are incorporated partly at the expense of AA, but also of other n-6 fatty acids. EPA and DHA inhibit AA metabolism. Thus production of AA-derived eicosanoids is decreased by these n-3 fatty acids; this occurs in a dose-dependent manner. EPA gives rise to an alternative family of eicosanoids (e.g. PGE(3)), which frequently, but not always, have lower potency than those produced from AA. Recently a new family of EPA- and DHA-derived lipid mediators called resolvins (E- and D-series) has been described. These have potent anti-inflammatory and inflammation resolving properties in model systems. It seems likely that these mediators will explain many of the antiinflammatory actions of n-3 fatty acids that have been described. In addition to modifying the profile of lipid-derived mediators, fatty acids can also influence peptide mediator (i.e. cytokine) production. To a certain extent this action may be due to the altered profile of regulatory eicosanoids, but it seems likely that eicosanoid-independent actions are a more important mechanism. Indeed effects on transcription factors that regulate inflammatory gene expression (e.g. nuclear factor kappaB) seem to be important.