We examined the effects of dietary n-3 polyunsaturated and saturated fatty acids on the development of the atherogenic process in mice and on the macrophage ability to secrete several effector molecules that may be involved in the atherogenic process. The secretion of inflammatory proteins such as tumor necrosis factor-* (TNF-<*) and interleukin-1/3 (IL-10) and the production of lipoprotein lipase (LPL), nitrogen oxide (NO2), and prostaglandin Ej (PGEJ were evaluated in peritoneal macrophages isolated from atherosclerosis-susceptible C57BIV6J mice. The mice were assigned at random to three experimental groups: the first group was fed a semi-defined control diet (control diet); the second group was maintained on the control diet supplemented with 10% menhaden oil (menhaden diet); and the third group received the control diet supplemented with 10% palm oil plus 2% cholesterol (saturated fat diet). Macrophages derived from mice fed the menhaden diet showed a suppression of their basal TNF-or mRNA expression and production. They also presented a dramatically decreased ability to express TNF-aand IL-10 raRNAs in response to exposure to lipopolysaccharide (LPS) compared with the macrophages from the control group. LPL mRNA and protein expression were downregulated after 6 and 15 weeks of menhaden-diet feeding. Significantly higher NO2production in response to interferon gamma was found, both after 6 and 15 weeks of diet feeding, in the menhaden group compared with the control group. In addition, prostaglandin production and macrophage tumoricidal activity in response to LPS were decreased in this group compared with the control group. Macrophages derived from the saturated fat group did not show any significant alterations in TNF-a, LPL, NO2, or PGE? secretion compared with controls. Interestingly, we observed a progressive increase of the LPS-induced IL-1/3 gene expression and secretion among macrophages harvested from mice receiving the dietary supplement of saturated fatty acids. At 6 and 15 weeks histologic examination of the atherosclerotic lesions did not reveal any important lesions in the control and menhaden groups, whereas a gradual development of fatty streaks was observed in the saturated fat group. After 15 weeks of diet, the addition of saturated fatty acids to the control and menhaden experimental diets for 10 additional weeks resulted in a major development of lesions in the control group, whereas only slight lesions were observed in the menhaden group. These data indicated a beneficial effect of dietary n-3 polyunsaturated fatty acids on the development of atherosclerosis and underlined possible involvement of cytokines in atherogenesis.