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. 1989 Mar;86(5):1657–1661. doi: 10.1073/pnas.86.5.1657

Temporal and pharmacological division of fibroblast cyclooxygenase expression into transcriptional and translational phases.

A Raz 1, A Wyche 1, P Needleman 1
PMCID: PMC286758  PMID: 2493647

Abstract

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.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aarsman A. J., Mynbeek G., van den Bosch H., Rothhut B., Prieur B., Comera C., Jordan L., Russo-Marie F. Lipocortin inhibition of extracellular and intracellular phospholipases A2 is substrate concentration dependent. FEBS Lett. 1987 Jul 13;219(1):176–180. doi: 10.1016/0014-5793(87)81212-7. [DOI] [PubMed] [Google Scholar]
  2. Albrightson C. R., Baenziger N. L., Needleman P. Exaggerated human vascular cell prostaglandin biosynthesis mediated by monocytes: role of monokines and interleukin 1. J Immunol. 1985 Sep;135(3):1872–1877. [PubMed] [Google Scholar]
  3. Brönnegård M., Andersson O., Edwall D., Lund J., Norstedt G., Carstedt-Duke J. Human calpactin II (lipocortin I) messenger ribonucleic acid is not induced by glucocorticoids. Mol Endocrinol. 1988 Aug;2(8):732–739. doi: 10.1210/mend-2-8-732. [DOI] [PubMed] [Google Scholar]
  4. Burch R. M., Axelrod J. Dissociation of bradykinin-induced prostaglandin formation from phosphatidylinositol turnover in Swiss 3T3 fibroblasts: evidence for G protein regulation of phospholipase A2. Proc Natl Acad Sci U S A. 1987 Sep;84(18):6374–6378. doi: 10.1073/pnas.84.18.6374. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chamberlain J. P. Fluorographic detection of radioactivity in polyacrylamide gels with the water-soluble fluor, sodium salicylate. Anal Biochem. 1979 Sep 15;98(1):132–135. doi: 10.1016/0003-2697(79)90716-4. [DOI] [PubMed] [Google Scholar]
  6. Colamonici O. R., Trepel J. B., Vidal C. A., Neckers L. M. Phorbol ester induces c-sis gene transcription in stem cell line K-562. Mol Cell Biol. 1986 May;6(5):1847–1850. doi: 10.1128/mcb.6.5.1847. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Davidson F. F., Dennis E. A., Powell M., Glenney J. R., Jr Inhibition of phospholipase A2 by "lipocortins" and calpactins. An effect of binding to substrate phospholipids. J Biol Chem. 1987 Feb 5;262(4):1698–1705. [PubMed] [Google Scholar]
  8. Davidson F. F., Dennis E. A., Powell M., Glenney J. R., Jr Inhibition of phospholipase A2 by "lipocortins" and calpactins. An effect of binding to substrate phospholipids. J Biol Chem. 1987 Feb 5;262(4):1698–1705. [PubMed] [Google Scholar]
  9. Fan X. D., Goldberg M., Bloom B. R. Interferon-gamma-induced transcriptional activation is mediated by protein kinase C. Proc Natl Acad Sci U S A. 1988 Jul;85(14):5122–5125. doi: 10.1073/pnas.85.14.5122. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Flower R. J. Eleventh Gaddum memorial lecture. Lipocortin and the mechanism of action of the glucocorticoids. Br J Pharmacol. 1988 Aug;94(4):987–1015. doi: 10.1111/j.1476-5381.1988.tb11614.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Goerig M., Habenicht A. J., Heitz R., Zeh W., Katus H., Kommerell B., Ziegler R., Glomset J. A. sn-1,2-Diacylglycerols and phorbol diesters stimulate thromboxane synthesis by de novo synthesis of prostaglandin H synthase in human promyelocytic leukemia cells. J Clin Invest. 1987 Mar;79(3):903–911. doi: 10.1172/JCI112900. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Goppelt-Strübe M., Pfannkuche H. J., Gemsa D., Resch K. The diacylglycerols dioctanoylglycerol and oleoylacetylglycerol enhance prostaglandin synthesis by inhibition of the lysophosphatide acyltransferase. Biochem J. 1987 Nov 1;247(3):773–777. doi: 10.1042/bj2470773. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Greenberg M. E., Ziff E. B. Stimulation of 3T3 cells induces transcription of the c-fos proto-oncogene. Nature. 1984 Oct 4;311(5985):433–438. doi: 10.1038/311433a0. [DOI] [PubMed] [Google Scholar]
  14. Hidaka H., Inagaki M., Kawamoto S., Sasaki Y. Isoquinolinesulfonamides, novel and potent inhibitors of cyclic nucleotide dependent protein kinase and protein kinase C. Biochemistry. 1984 Oct 9;23(21):5036–5041. doi: 10.1021/bi00316a032. [DOI] [PubMed] [Google Scholar]
  15. Kelly K., Cochran B. H., Stiles C. D., Leder P. Cell-specific regulation of the c-myc gene by lymphocyte mitogens and platelet-derived growth factor. Cell. 1983 Dec;35(3 Pt 2):603–610. doi: 10.1016/0092-8674(83)90092-2. [DOI] [PubMed] [Google Scholar]
  16. Lefkowith J. B., Flippo V., Sprecher H., Needleman P. Paradoxical conservation of cardiac and renal arachidonate content in essential fatty acid deficiency. J Biol Chem. 1985 Dec 15;260(29):15736–15744. [PubMed] [Google Scholar]
  17. Moore P. K., Hoult J. R. Anti-inflammatory steroids reduce tissue PG synthetase activity and enhance PG breakdown. Nature. 1980 Nov 20;288(5788):269–270. doi: 10.1038/288269a0. [DOI] [PubMed] [Google Scholar]
  18. Nishizuka Y. Studies and perspectives of protein kinase C. Science. 1986 Jul 18;233(4761):305–312. doi: 10.1126/science.3014651. [DOI] [PubMed] [Google Scholar]
  19. Parker J., Daniel L. W., Waite M. Evidence of protein kinase C involvement in phorbol diester-stimulated arachidonic acid release and prostaglandin synthesis. J Biol Chem. 1987 Apr 15;262(11):5385–5393. [PubMed] [Google Scholar]
  20. Pash J. M., Bailey J. M. Inhibition by corticosteroids of epidermal growth factor-induced recovery of cyclooxygenase after aspirin inactivation. FASEB J. 1988 Jul;2(10):2613–2618. doi: 10.1096/fasebj.2.10.2968288. [DOI] [PubMed] [Google Scholar]
  21. Raz A., Wyche A., Siegel N., Needleman P. Regulation of fibroblast cyclooxygenase synthesis by interleukin-1. J Biol Chem. 1988 Feb 25;263(6):3022–3028. [PubMed] [Google Scholar]
  22. Russo-Marie F., Duval D. Dexamethasone-induced inhibition of prostaglandin production dose not result from a direct action on phospholipase activities but is mediated through a steroid-inducible factor. Biochim Biophys Acta. 1982 Jul 20;712(1):177–185. doi: 10.1016/0005-2760(82)90100-x. [DOI] [PubMed] [Google Scholar]
  23. Whiteley P. J., Needleman P. Mechanism of enhanced fibroblast arachidonic acid metabolism by mononuclear cell factor. J Clin Invest. 1984 Dec;74(6):2249–2253. doi: 10.1172/JCI111651. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Wood J. N., Coote P. R., Rhodes J. Hydrocortisone inhibits prostaglandin production but not arachidonic acid release from cultured macrophages. FEBS Lett. 1984 Aug 20;174(1):143–146. doi: 10.1016/0014-5793(84)81093-5. [DOI] [PubMed] [Google Scholar]
  25. Zucali J. R., Dinarello C. A., Oblon D. J., Gross M. A., Anderson L., Weiner R. S. Interleukin 1 stimulates fibroblasts to produce granulocyte-macrophage colony-stimulating activity and prostaglandin E2. J Clin Invest. 1986 Jun;77(6):1857–1863. doi: 10.1172/JCI112512. [DOI] [PMC free article] [PubMed] [Google Scholar]

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