on July 1, 2004
Published online before print July 1, 2004, doi: 10.1161/01.ATV.0000137191.02577.86
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Submitted on March 10, 2004
Accepted on May 25, 2004
Oxidized Omega-3 Fatty Acids Inhibit NF-
B Activation Via a PPAR
-Dependent Pathway
Archana Mishra ;
From the Department of Pathology, University of Iowa Hospitals and Clinics, Iowa City, Iowa.
* To whom correspondence should be addressed. E-mail: sanjeev-sethi{at}uiowa.edu.
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.
Methods and 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-
B (NF-B). Using Western blot analyses, we show that the inhibition of NF-B activation was not caused by prevention of phosphorylation of IB
because oxidized EPA did not inhibit cytokine-induced phosphorylation and ubiquination of IB. Furthermore, oxidized EPA inhibited NF-B activation in endothelial cells derived from wild-type mice but had no inhibitory effects on NF-B activation in endothelial cells derived from peroxisome proliferator-activated receptor (PPAR)-deficient mice, indicating that oxidized EPA requires PPAR for its inhibitory effects on NF-B.
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-B activation via a PPAR-dependent pathway.
Key words: monocyte chemoattractant protein-1 • oxidized omega-3 fatty acids • oxidized eicosapentaenoic acid • nuclear factor-
B •
PPARa
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