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Dietary-induced changes in tissue levels of polyunsaturated fatty acids modify inflammatory reactions through changes in the synthesis of lipid and peptide mediators of inflammation. Four semipurified 20% fat diets, based on beef tallow (BT), safflower oil (SFO), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) were provided. The DHA and EPA ratios of the (n-3) fatty acid-based diets were 1.1 and 3.4, respectively. The effect of prefeeding diets differing in EPA to DHA ratios prior to the induction of streptococcal cell wall (SCW) arthritis in female Lew/SSN rats was examined. Weanling rats were fed diets for 5 wk before arthritis induction and 5 wk post-arthritis induction. Footpad thickness, hock circumference, plasma and macrophage fatty acids and histological assessment were compared. There were no differences in food intake and final body weights among the groups. Footpad inflammation, reported as percentage change (adjusted for growth) was greatest for rats fed the BT-based diet, intermediate in those fed the SFO-based diet and least for the rats fed the EPA- and DHA-based diets (P < 0.05). Macrophage phospholipids revealed cellular incorporation of EPA and DHA from the fish-oil based diets which modified lipid and peptide mediators of inflammation. Histological sections of rat hocks ranked by severity of arthritis-related changes suggested that the SFO- and EPA-based diets were more successful in ameliorating the destructive arthritic phase in hock joints than the BT- and DHA-based diets (P = 0.09) in this model of arthritis. The course of SCW-induced arthritis can be altered by diet-induced changes in macrophage fatty acid composition. The EPA-based diet is more effective in suppression of inflammation than the DHA-based diet. [ABSTRACT FROM AUTHOR]