INFLUENCE OF UNSATURATED FATTY-ACIDS ON THE PRODUCTION OF TUMOR-NECROSIS-FACTOR AND INTERLEUKIN-6 BY RAT PERITONEAL-MACROPHAGES

The effect of individual unsaturated fatty acids on the release of tum our necrosis factor (TNF) and interleukin 6 (IL6) was investigated in thioglycollate - induced rat peritoneal macrophages. The intracellular mechanisms associated with the changes of cytokine production in resp onse to fatty acids were also studied. Incubation of macrophages with 100 mu M docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) in creased TNF (21% and 15% respectively) and IL6 (69% and 40% respective ly) production. Linoleic acid (LA) diminished TNF production by 16%. A t 100 mu M oleic acid (OA), LA and EPA concentration an increase in ma crophage adenylate cyclase activity (110%, 72% and 39% respectively) a nd a decrease (14%) in the presence of DHA was observed. PGE(2) produc tion in the presence of 100 mu M DHA was reduced by 36%, whereas in th e presence of 100 mu M LA an increase (75%) was observed. Phospholipas e A(2) (PLA(2)) activity was also found to be modified in the presence of EPA and DHA at 50 mu M (20% and 60% respectively) and 100 mu M (34 % and 62% respectively) concentrations. The activities of both protein kinase A (PKA) and protein kinase C (PKC) were effected by the differ ent fatty acids. At 50 mu M all fatty acids suppressed PKA activity ex cept OA which enhanced PKA activity by 14%. At 100 mu M fatty acid con centration, EPA suppressed PKA activity by 40%. PKC activity was enhan ced by LA and OA, by 18% and 21% respectively. However, at 100 mu M EP A and DHA, PKC activity was suppressed by 37% and 17% respectively, wh ereas PKC activity was enhanced by 146% in the presence of 100 mu M LA . These results show for the first time that unsaturated fatty acids h ave an effect on macrophage PLA(2) activity and that PGE(2) may be a p otent modulator of IL6 production. From these studies it is tempting t o speculate that macrophage TNF and IL6 release may, in part, occur vi a a PKC and PKA independent pathway and that PLA(2) activity and PGE(2 ) concentration are inversely related to production of TNF and IL6.