Temporal and pharmacological division of fibroblast cyclooxygenase expression into transcriptional and translational phases.
We have recently shown that the synthesis of cyclooxygenase [also called prostaglandin (PG) synthase or PG endoperoxide synthase; 8,11,14-icosatrienoate, hydrogen-donor:oxygen oxidoreductase, EC 1.14.99.1] in human dermal fibroblasts is markedly stimulated by the cytokine interleukin 1 (IL-1). We now show that the temporal sequence of the induced synthesis of PG synthase can be separated into an early transcriptional (i.e., actinomycin D inhibitable) phase and a subsequent translational (cycloheximide but not actinomycin D inhibitable) phase and that IL-1 exerts its effect during the transcriptional phase. Phorbol 12-myristate 13-acetate also stimulates synthesis of PG synthase and, together with IL-1, produces a synergistic stimulatory effect. Inhibitors of protein kinase C activation abolished the stimulatory effect of IL-1, suggesting that protein kinase C activation is a critical event in the signal-transduction sequence of the IL-1-induced increase of PG synthase synthesis. The antiinflammatory glucocorticosteroids dexamethasone and triamcinolone, but not progesterone or testosterone, were potent inhibitors of PG synthase synthesis (complete inhibition at 20 nM; IC50, 1 nM) when added during the translational phase of the synthesis sequence. The glucocorticosteroid effect was blocked by RNA and protein synthesis inhibitors. This report suggests that glucocorticosteroids exert their effect via a newly synthesized protein, causing a profound translational control of PG synthase synthesis. This novel mechanism of suppression of arachidonate metabolism is distinct from any influence of steroids on phospholipase A2 activity.
Raz
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Department of Pharmacology, Washington University School of Medicine, Saint Louis, MO 63110.
Wyche
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Needleman
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D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives; D002118:Calcium / Q000037:antagonists & inhibitors; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D007700:Kinetics; D010879:Piperazines / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis / Q000235:genetics*; D014176:Protein Biosynthesis; D047428:Protein Kinase Inhibitors; D012867:Skin / Q000166:cytology / Q000201:enzymology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic
D007375:Interleukin-1; D007546:Isoquinolines; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D003907:Dexamethasone; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D011451:Prostaglandin-Endoperoxide Synthases; D013755:Tetradecanoylphorbol Acetate; C049347:fasudil; D002118:Calcium