EFFECTS OF DIFFERENT POLYUNSATURATED FATTY-ACIDS ON GROWTH-RELATED EARLY GENE-EXPRESSION AND CELL-GROWTH

Effects of polyunsaturated fatty acids on expression of early-response genes c-fos and Egr-1 and induction of cell growth were assessed in S wiss 3T3 fibroblasts. Stimulation with arachidonic acid increased mRNA levels of c-fos and Egr-1. This effect was inhibited by preincubation with cyclooxygenase inhibitors and restored by addition of prostaglan din E(2) (PGE(2)), the predominant eicosanoid produced in Swiss 3T3 fi broblasts. Further signaling of PGE(2) was mediated by a protein kinas e C-dependent pathway, since downregulation, or inhibition, of protein kinase C reduced increases in mRNA levels. Parallel to the stimulator y effects on mRNA levels, AA and PGE(2) also increased cell growth, as determined by uptake of [H-3]-thymidine. In contrast to arachidonic a cid, n-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic a cid (DHA) did not increase c-fos and Egr-1 mRNA levels or cell growth. Furthermore, preliminary data indicate that EPA and DHA even reduce t he stimulatory effect of AA, which is associated with reduced formatio n of PGE(2). In conclusion, our data indicate that AA increases expres sion of growth-related early genes c-fos and Egr-1 in Swiss 3T3 fibrob lasts by its conversion to PGE(2) and subsequent activation of protein kinase C, whereas n-3 fatty acids do not activate this signaling casc ade.