EVIDENCE FOR THE INVOLVEMENT OF 5-LIPOXYGENASE PRODUCTS IN THE REGULATION OF THE EXPRESSION OF THE PROENKEPHALIN GENE IN CULTURED ASTROGLIAL CELLS

Cultured astroglial cells secrete eicosanoids which are produced by th e cyclooxygenase and lipoxygenases. These cells also transcribe the pr oenkephalin gene. In the present study, it was investigated whether ag ents which inhibit the metabolism of arachidonic acid affect the basal and stimulated expression of the gene. Tetradecanoyl phorbol acetate (TPA; 1-1000 nmol/l) increases the concentration of proenkephalin mRNA in these cells by activating protein kinase C. The enhancement in pro enkephalin mRNA caused by TPA (10 nmol/l) was not affected by the cycl ooxygenase inhibitor indomethacin (5 mu mol/l). However, nordihydrogua iaretic acid, which blocks cyclooxygenase and lipoxygenases, potentiat ed the effect of TPA on proenkephalin mRNA, when used at concentration s of 0.5-50 mu mol/l. Two selective inhibitors of 5-lipoxygenase, i.e. MK886 (5 mu mol/l) and BAY X1005 (1 mu mol/l), also enhanced the effe ct of TPA (10 nmol/l) without affecting the basal expression of the ge ne. When added to the incubation medium, leukotriene E(4) (10-1000 nmo l/l) diminished in a dose-dependent manner the basal and TPA-induced e xpression of the proenkephalin gene. It is concluded that in astroglia l cells derived from cortex of new-born rats products of 5-lipoxygenas e can diminish the action of protein kinase C on the proenkephalin gen e.