Inhibition of leukocyte-endothelial interactions by oxidized omega-3 fatty acids: a novel mechanism for the anti-inflammatory effects of omega-3 fatty acids in fish oil

Omega-3 fatty acids which are abundant in fish oil improve the prognosis of several chronic inflammatory diseases that are characterized by leukocyte-mediated tissue injury. The omega-3 fatty acids, such as eicosapentaenoic acid (EPA), are highly polyunsaturated and readily undergo oxidation. Our data suggest that the beneficial effects of fish oil may be due to the oxidative modification of omega-3 fatty acids. The oxidized products inhibit leukocyte adhesion receptor expression and leukocyte-endothelial interactions. Oxidized EPA is a potent inhibitor of leukocyte interactions with the endothelium compared to native EPA, both in vitro and in an in vivo context of inflammation. The effects of oxidized EPA are mediated through activation of PPARalpha and subsequent inhibition of NF-kappaB, leading to the down-regulation of leukocyte adhesion receptor expression required for leukocyte-endothelial interactions. We propose that oxidation of EPA and its activation of PPARalpha and subsequent inhibition of NF-kappaB is the underlying mechanism for the beneficial effects of fish oil.