A role for protein kinase C alpha in stimulation of prostaglandin G/H synthase-2 transcription by 14,15-epoxyeicosatrienoic acid

Abstract

Arachidonic acid, but not eicosapentaenoic acid, increased prostaglandin G/H endoperoxide synthase-2 transcription in cultured intestinal epithelial cells. This stimulatory effect on PGHS-2 synthesis was prevented by an AA utilization inhibitor, eicosatetraynoic acid. Specific inhibitors of the cyclooxygenase or the lipoxygenase pathways of AA metabolism did not prevent AA-mediated induction of PGHS-2 synthesis; however, the involvement of cytochrome P450 monoxygenases (CYP450) was indicated as several CYP450 blockers, ketoconazole, miconazole, and metyrapone, inhibited the induction of PGHS-2 mRNA synthesis by AA. This blockade by CYP450 inhibitors could be overcome by the addition of the AA epoxygenase metabolite 14,15-epoxyeicosatrienoic acid (14,15-EET); other EET regio-isomers were unable to elevate PGHS-2 mRNA level. Blockade of protein kinase C with a specific inhibitor, bisindolyl maleimide-1, or translational inhibition of protein kinase C alpha by antisense oligonucleotides reduced PGHS-2 transcription, suggesting the involvement of protein kinase C alpha in the signal transduction pathway.