DIFFERENTIAL-EFFECTS OF N-6 AND N-3 POLYUNSATURATED FATTY-ACIDS ON CELL-GROWTH AND EARLY GENE-EXPRESSION IN SWISS 3T3 FIBROBLASTS

Dietary n-3 polyunsaturated fatty acids (PUFAs) have been found to red uce accelerated cell growth. To study the underlying molecular mechani sms, we evaluated the effects of the n-3 PUFAs eicosapentaenoic acid ( EPA) and docosahexaenoic acid (DHA) compared with the n-6 PUFA arachid onic acid (AA) on cell growth and early gene mRNA accumulation in Swis s 3T3 fibroblasts. AA significantly increased cell numbers and incorpo ration of [H-3]-thymidine compared with cells treated with EPA and DHA , which did not stimulate cell growth. In contrast to AA and parallel to its effect on cell growth, EPA and DHA did not lead to a pronounced increase in Egr-1 and c-fos mRNA levels. When they were incubated tog ether with AA, both DHA and EPA reduced AA-induced Egr-1 and c-fos mRN A accumulation and incorporation of H-3]-thymidine. We have recently s hown that AA strongly increases Egr-1 and c-fos mRNA accumulation in 3 T3 fibroblasts through its metabolism to prostaglandin E(2) (PGE(2)) a nd its subsequent activation of protein kinase C (Danesch et al., 1994 , J. Biol. Chem., 269:27258-27263). Consistent with the notion that in creased PGE(2) formation is required for the AA-induced early gene mRN A accumulation, EPA and DHA reduced PGE(2) formation from exogenous [C -14]-AA by more than 60%, but they did not decrease mRNA levels follow ing stimulation with PGE(2). We suggest that, in 3T3 fibroblasts, EPA and DHA antagonize AA-induced early gene mRNA accumulation and cell gr owth by reducing PGE(2) formation. (C) 1996 Wiley-Liss, Inc.