title: Oxidized omega-3 fatty acids inhibit NF-kappaB activation via a PPARalpha-dependent pathway.
abstract: OBJECTIVE
  The aim of this study was to determine the effects of oxidized versus native omega-3 fatty acids on the endothelial expression of chemokines MCP-1 and IL-8, and, if effective in inhibiting chemokine expression, to determine the mechanism for the inhibition of chemokine expression.
  
  
  RESULTS
  Using enzyme-linked immunosorbent assays, we show that oxidized EPA and DHA but not unoxidized EPA or DHA inhibit cytokine-induced endothelial expression of monocyte chemoattractant protein (MCP)-1 and, to a lesser extent, IL-8. In electrophoretic mobility shift assays, oxidized EPA but not unoxidized EPA potently inhibited cytokine-induced activation of endothelial nuclear factor-kappaB (NF-kappaB). Using Western blot analyses, we show that the inhibition of NF-kappaB activation was not caused by prevention of phosphorylation of IkappaBalpha because oxidized EPA did not inhibit cytokine-induced phosphorylation and ubiquination of IkappaBalpha. Furthermore, oxidized EPA inhibited NF-kappaB activation in endothelial cells derived from wild-type mice but had no inhibitory effects on NF-kappaB activation in endothelial cells derived from peroxisome proliferator-activated receptor alpha (PPARalpha)-deficient mice, indicating that oxidized EPA requires PPARalpha for its inhibitory effects on NF-kappaB.
  
  
  CONCLUSIONS
  These studies show that the antiinflammatory effects of fish oil may result from the inhibitory effects of oxidized omega-3 fatty acids on NF-kappaB activation via a PPARalpha-dependent pathway.
authors.affiliation: Department of Pathology, 5243 RCP, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242, USA.
authors.forename: Archana
authors.initials: A
authors.lastname: Mishra
authors.forename: Ashok
authors.initials: A
authors.lastname: Chaudhary
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Sethi
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology; D001011:Aorta; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D018932:Chemokine CCL2 / Q000096:biosynthesis* / Q000235:genetics; D004281:Docosahexaenoic Acids / Q000737:chemistry / Q000494:pharmacology*; D015118:Eicosapentaenoic Acid / Q000737:chemistry / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D007375:Interleukin-1; D016209:Interleukin-8; D016328:NF-kappa B; D047493:PPAR alpha; D014409:Tumor Necrosis Factor-alpha; D004281:Docosahexaenoic Acids; D015118:Eicosapentaenoic Acid