Oxidized omega-3 fatty acids inhibit pro-inflammatory responses in glomerular endothelial cells.
BACKGROUND
Omega-3 fatty acids have beneficial effects in chronic inflammatory diseases that are characterized by accumulation of leukocytes and leukocyte-mediated tissue injury. Accumulation of leukocytes occurs, in part, due to pro-inflammatory responses in endothelial cells, such as increase in expression of leukocyte adhesion receptors and chemokines, such as MCP-1 and IL-8.


METHODS
omega-3 fatty acids, such as EPA, are highly polyunsaturated and readily undergo auto-oxidation. We studied the effect of oxidized EPA and unoxidized (native) EPA on leukocyte-glomerular endothelial cell interactions using adhesion assays, ELISA assays and transmigration assays. We used electrophoresis mobility shift assays to determine the effect of oxidized and unoxidized EPA on cytokine-induced nuclear factor-kappaB (NF-kappaB) activation.


RESULTS
Oxidized EPA but not unoxidized EPA dose-dependently inhibits cytokine-induced leukocyte adhesion receptors on glomerular endothelial cells, which correlates with inhibition of leukocyte-glomerular endothelial cell interactions. Oxidized EPA but not unoxidized EPA inhibits cytokine-induced glomerular endothelial and mesangial cell expression of MCP-1, and to a lesser extent IL-8. Transmigration assays show that oxidized EPA but not unoxidized EPA inhibits leukocyte transmigration across glomerular endothelial cells. Oxidized EPA but not unoxidized EPA potently inhibited cytokine-induced activation of NF-kappaB in glomerular endothelial and mesangial cells.


CONCLUSIONS
These studies show that the beneficial effects of fish oil in chronic inflammatory diseases, including IgA nephropathy, may result from the inhibitory effects of oxidized omega-3 fatty acids on pro-inflammatory events in endothelial cells via inhibition of NF-kappaB activation.
Chaudhary
Ashok
A
Department of Pathology, University of Iowa of Iowa Hospitals and Clinics, Iowa City, Iowa 52242, USA.
Mishra
Archana
A
Sethi
Sanjeev
S
D002196:Capillaries; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D018932:Chemokine CCL2 / Q000096:biosynthesis; D003331:Coronary Vessels; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000502:physiology; D015118:Eicosapentaenoic Acid / Q000378:metabolism / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D015525:Fatty Acids, Omega-3 / Q000494:pharmacology*; D005920:Glomerular Mesangium / Q000098:blood supply / Q000166:cytology / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis; D007678:Kidney Glomerulus / Q000098:blood supply / Q000166:cytology* / Q000187:drug effects; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology; D010084:Oxidation-Reduction; D020298:U937 Cells / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis
D018932:Chemokine CCL2; D016207:Cytokines; D015525:Fatty Acids, Omega-3; D016328:NF-kappa B; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D015118:Eicosapentaenoic Acid