Diaz Encarnacion MM, Warner GM, Cheng J, Gray CE, Nath KA, Grande JP. n-3 Fatty acids block TNF-alpha-stimulated MCP-1 expression in rat mesangial cells. Am J Physiol Renal Physiol 300: F1142-F1151, 2011. First published March 2, 2011; doi:10.1152/ajprenal.00064.2011.-Monocyte chemoattractant protein 1 (MCP-1) is a CC cytokine that fundamentally contributes to the pathogenesis of inflammatory renal disease. MCP-1 is highly expressed in cytokine-stimulated mesangial cells in vitro and following glomerular injury in vivo. Interventions to limit MCP-1 expression are commonly effective in assorted experimental models. Fish oil, an abundant source of n-3 fatty acids, has anti-inflammatory properties, the basis of which remains incompletely defined. We examined potential mechanisms whereby fish oil reduces MCP-1 expression and thereby suppresses inflammatory responses to tissue injury. Cultured mesangial cells were treated with TNF-alpha in the presence of the n-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA); equimolar concentrations of the n-6 fatty acids LA and OA served as controls. MCP-1 mRNA expression was assessed by Northern blotting, and transcriptional activity of the MCP-1 promoter was assessed by transient transfection. The involvement of the ERK and NF-kappa B pathways was evaluated through transfection analysis and the use of the MEK inhibitor U0126. DHA and EPA decreased TNF-alpha-stimulated MCP-1 mRNA expression by decreasing transcription of the MCP-1 gene. DHA and EPA decreased p-ERK expression and nuclear translocation of NF-kappa B, both of which are necessary for TNF-alpha-stimulated MCP-1 expression. Both NF-kappa B and AP-1 sites were involved in transcriptional regulation of the MCP-1 gene by DHA and EPA. We conclude that DHA and EPA inhibit TNF-alpha-stimulated transcription of the MCP-1 gene through interaction of signaling pathways involving ERK and NF-kappa B. We speculate that such effects may contribute to the salutary effect of fish oil in renal and vascular disease.