EFFECTS OF IN-VITRO EXPOSURE TO ARACHIDONIC-ACID ON TNF-ALPHA PRODUCTION BY MURINE PERITONEAL-MACROPHAGES

Modifying the fatty acid composition of macrophages through diet can s ignificantly alter some of their functions, such as tumoricidal capaci ty and tumor necrosis factor alpha (TNF-alpha) production. The mechani sm of that modification, however, is unknown. In this report, we provi de evidence that fatty acids added to macrophages in culture can signi ficantly alter macrophage TNF-alpha production. For example when infla mmatory macrophages were incubated with various doses of arachidonic a cid [20:4(n-6)] during activation with lipopolysaccharide (LPS), we ob served a dose-dependent decrease in the level of bioactive TNF-alpha w ith complete inhibition at 2-5 muM. This inhibition was specific for 2 0:4(n-6) because in vitro treatment with other fatty acids, such as ei cosapentaenoic [20:5(n-3)] or docosahexaenoic [22:6(n-3)] acids, had d ifferential effects. The inhibitory action of 20:4(n-6) did not involv e toxicity because cell viability was not affected and in vitro interf eron-gamma and lipopolysaccharide (LPS) activation of macrophages for killing of P815 tumor targets was not altered. Inhibition by 20:4(n-6) occurred posttranscriptionally, and could be reversed when macrophage s were treated with indomethacin during activation. Arachidonic acid t reatment also significantly increased the production of immunoreactive prostaglandin E2 (PGE2) by LPS-treated and untreated macrophages. The se results suggest that in vitro treatment of macrophages with 20:4(n- 6) may inhibit TNF-alpha production through an alteration in the level s of PGE2 at a posttranscriptional level. These results provide eviden ce that some dietary fats may affect macrophage activity through modif ication of eicosanoid synthesis.