Skip to main content
PMC home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1990 Sep;87(18):6974–6978. doi: 10.1073/pnas.87.18.6974

Inhibition of eicosanoid biosynthesis by glucocorticoids in humans.

R J Sebaldt 1, J R Sheller 1, J A Oates 1, L J Roberts 2nd 1, G A FitzGerald 1
PMCID: PMC54664  PMID: 2169616

Abstract

Therapeutic doses of glucocorticoids are thought to inhibit prostaglandin and leukotriene formation in humans. Several studies in animals, however, have failed to demonstrate modulation of eicosanoid biosynthesis by steroids in vivo. We administered prednisone (60 mg/day) to eight healthy volunteers and measured eicosanoid formation by a variety of cell types in vivo and ex vivo, using sensitive and specific physicochemical assays. We found that the in vivo course of prednisone failed to inhibit the synthesis of thromboxane A2, prostaglandin I2 (prostacyclin), prostaglandin E2, and leukotriene E4 in vivo and of leukotriene B4 ex vivo. Biosynthesis of leukotriene B4, thromboxane B2, and prostaglandins F2 and E2 by macrophage-rich bronchoalveolar lavage cells was strongly suppressed. These findings indicate that therapeutic regimens of glucocorticoids suppress eicosanoid biosynthesis in human macrophages but not in a number of other cell types with steroid receptors, the capacity for eicosanoid formation, and lipocortin-like material.

Full text

PDF
6974

Selected References

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

  1. Armanini D., Strasser T., Weber P. C. Parallel determination of glucocorticoid receptors in human mononuclear and polymorphonuclear leukocytes after Percoll separation. J Endocrinol Invest. 1985 Feb;8(1):45–47. doi: 10.1007/BF03350637. [DOI] [PubMed] [Google Scholar]
  2. Balter M. S., Eschenbacher W. L., Peters-Golden M. Arachidonic acid metabolism in cultured alveolar macrophages from normal, atopic, and asthmatic subjects. Am Rev Respir Dis. 1988 Nov;138(5):1134–1142. doi: 10.1164/ajrccm/138.5.1134. [DOI] [PubMed] [Google Scholar]
  3. Bienkowski M. J., Petro M. A., Robinson L. J. Inhibition of thromboxane A synthesis in U937 cells by glucocorticoids. Lack of evidence for lipocortin 1 as the second messenger. J Biol Chem. 1989 Apr 15;264(11):6536–6544. [PubMed] [Google Scholar]
  4. Catella F., FitzGerald G. A. Paired analysis of urinary thromboxane B2 metabolites in humans. Thromb Res. 1987 Sep 15;47(6):647–656. doi: 10.1016/0049-3848(87)90103-4. [DOI] [PubMed] [Google Scholar]
  5. Cirino G., Sorrentino L. Phospholipase inhibition and prostacyclin generation by gastric muscularis and mucosa layers. Agents Actions. 1986 Aug;18(5-6):535–537. doi: 10.1007/BF01964960. [DOI] [PubMed] [Google Scholar]
  6. Crutchley D. J., Ryan U. S., Ryan J. W. Glucocorticoid modulation of prostacyclin production in cultured bovine pulmonary endothelial cells. J Pharmacol Exp Ther. 1985 Jun;233(3):650–655. [PubMed] [Google Scholar]
  7. De Caterina R., Weksler B. B. Modulation of arachidonic acid metabolism in human endothelial cells by glucocorticoids. Thromb Haemost. 1986 Jun 30;55(3):369–374. [PubMed] [Google Scholar]
  8. De B. K., Misono K. S., Lukas T. J., Mroczkowski B., Cohen S. A calcium-dependent 35-kilodalton substrate for epidermal growth factor receptor/kinase isolated from normal tissue. J Biol Chem. 1986 Oct 15;261(29):13784–13792. [PubMed] [Google Scholar]
  9. Di Rosa M., Calignano A., Carnuccio R., Ialenti A., Sautebin L. Multiple control of inflammation by glucocorticoids. Agents Actions. 1986 Jan;17(3-4):284–289. doi: 10.1007/BF01982621. [DOI] [PubMed] [Google Scholar]
  10. Di Rosa M., Persico P. Mechanism of inhibition of prostaglandin biosynthesis by hydrocortisone in rat leucocytes. Br J Pharmacol. 1979 Jun;66(2):161–163. doi: 10.1111/j.1476-5381.1979.tb13659.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Dworski R., Sheller J. R., Wickersham N. E., Oates J. A., Brigham K. L., Roberts L. J., 2nd, Fitzgerald G. A. Allergen-stimulated release of mediators into sheep bronchoalveolar lavage fluid. Effect of cyclooxygenase inhibition. Am Rev Respir Dis. 1989 Jan;139(1):46–51. doi: 10.1164/ajrccm/139.1.46. [DOI] [PubMed] [Google Scholar]
  12. FitzGerald G. A., Oates J. A., Hawiger J., Maas R. L., Roberts L. J., 2nd, Lawson J. A., Brash A. R. Endogenous biosynthesis of prostacyclin and thromboxane and platelet function during chronic administration of aspirin in man. J Clin Invest. 1983 Mar;71(3):676–688. doi: 10.1172/JCI110814. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. FitzGerald G. A., Smith B., Pedersen A. K., Brash A. R. Increased prostacyclin biosynthesis in patients with severe atherosclerosis and platelet activation. N Engl J Med. 1984 Apr 26;310(17):1065–1068. doi: 10.1056/NEJM198404263101701. [DOI] [PubMed] [Google Scholar]
  14. Gerritsen M. E., Cheli C. D. Arachidonic acid and prostaglandin endoperoxide metabolism in isolated rabbit and coronary microvessels and isolated and cultivated coronary microvessel endothelial cells. J Clin Invest. 1983 Nov;72(5):1658–1671. doi: 10.1172/JCI111125. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gryglewski R. J., Panczenko B., Korbut R., Grodzinska L., Ocetkiewicz A. Corticosteroids inhibit prostaglandin release from perfused mesenteric blood vessels of rabbit and from perfused lungs of sensitized guinea pig. Prostaglandins. 1975 Aug;10(2):343–355. doi: 10.1016/0090-6980(75)90053-2. [DOI] [PubMed] [Google Scholar]
  16. Hales C. A., Brandstetter R. D., Neely C. F., Peterson M. B., Kong D., Watkins W. D. Methylprednisolone on circulating eicosanoids and vasomotor tone after endotoxin. J Appl Physiol (1985) 1986 Jul;61(1):185–191. doi: 10.1152/jappl.1986.61.1.185. [DOI] [PubMed] [Google Scholar]
  17. Hong S. L., Levine L. Inhibition of arachidonic acid release from cells as the biochemical action of anti-inflammatory corticosteroids. Proc Natl Acad Sci U S A. 1976 May;73(5):1730–1734. doi: 10.1073/pnas.73.5.1730. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Huang K. S., Wallner B. P., Mattaliano R. J., Tizard R., Burne C., Frey A., Hession C., McGray P., Sinclair L. K., Chow E. P. Two human 35 kd inhibitors of phospholipase A2 are related to substrates of pp60v-src and of the epidermal growth factor receptor/kinase. Cell. 1986 Jul 18;46(2):191–199. doi: 10.1016/0092-8674(86)90736-1. [DOI] [PubMed] [Google Scholar]
  19. Knapp H. R., Healy C., Lawson J., FitzGerald G. A. Effects of low-dose aspirin on endogenous eicosanoid formation in normal and atherosclerotic men. Thromb Res. 1988 May 1;50(3):377–386. doi: 10.1016/0049-3848(88)90267-8. [DOI] [PubMed] [Google Scholar]
  20. MacDermot J., Kelsey C. R., Waddell K. A., Richmond R., Knight R. K., Cole P. J., Dollery C. T., Landon D. N., Blair I. A. Synthesis of leukotriene B4, and prostanoids by human alveolar macrophages: analysis by gas chromatography/mass spectrometry. Prostaglandins. 1984 Feb;27(2):163–179. doi: 10.1016/0090-6980(84)90071-6. [DOI] [PubMed] [Google Scholar]
  21. Nasjletti A., Erman A., Cagen L. M., Baer P. G. Plasma concentrations, renal excretion, and tissue release of prostaglandins in the rat with dexamethasone-induced hypertension. Endocrinology. 1984 Mar;114(3):1033–1040. doi: 10.1210/endo-114-3-1033. [DOI] [PubMed] [Google Scholar]
  22. Nowak J., FitzGerald G. A. Redirection of prostaglandin endoperoxide metabolism at the platelet-vascular interface in man. J Clin Invest. 1989 Feb;83(2):380–385. doi: 10.1172/JCI113895. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Náray-Fejes-Tóth A., Fejes-Tóth G., Fischer C., Frölich J. C. Effect of dexamethasone on in vivo prostanoid production in the rabbit. J Clin Invest. 1984 Jul;74(1):120–123. doi: 10.1172/JCI111391. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Pawlowski N. A., Kaplan G., Hamill A. L., Cohn Z. A., Scott W. A. Arachidonic acid metabolism by human monocytes. Studies with platelet-depleted cultures. J Exp Med. 1983 Aug 1;158(2):393–412. doi: 10.1084/jem.158.2.393. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Peters-Golden M., Bathon J., Flores R., Hirata F., Newcombe D. S. Glucocorticoid inhibition of zymosan-induced arachidonic acid release by rat alveolar macrophages. Am Rev Respir Dis. 1984 Nov;130(5):803–809. doi: 10.1164/arrd.1984.130.5.803. [DOI] [PubMed] [Google Scholar]
  26. Peters-Golden M., Thebert P. Inhibition by methylprednisolone of zymosan-induced leukotriene synthesis in alveolar macrophages. Am Rev Respir Dis. 1987 May;135(5):1020–1026. doi: 10.1164/arrd.1987.135.5.1020. [DOI] [PubMed] [Google Scholar]
  27. Poubelle P. E., Borgeat P., Rola-Pleszczynski M. Assessment of leukotriene B4 synthesis in human lymphocytes by using high performance liquid chromatography and radioimmunoassay methods. J Immunol. 1987 Aug 15;139(4):1273–1277. [PubMed] [Google Scholar]
  28. Raz A., Wyche A., Needleman P. Temporal and pharmacological division of fibroblast cyclooxygenase expression into transcriptional and translational phases. Proc Natl Acad Sci U S A. 1989 Mar;86(5):1657–1661. doi: 10.1073/pnas.86.5.1657. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Reilly I. A., Knapp H. R., Fitzgerald G. A. Leukotriene B4 synthesis and neutrophil chemotaxis in chronic granulocytic leukaemia. J Clin Pathol. 1988 Nov;41(11):1163–1167. doi: 10.1136/jcp.41.11.1163. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Reines H. D., Halushka P. V., Cook J. A., Loadholt C. B. Lack of effect of glucocorticoids upon plasma thromboxane in patients in a state of shock. Surg Gynecol Obstet. 1985 Apr;160(4):320–322. [PubMed] [Google Scholar]
  31. Roy L., Knapp H. R., Robertson R. M., FitzGerald G. A. Endogenous biosynthesis of prostacyclin during cardiac catheterization and angiography in man. Circulation. 1985 Mar;71(3):434–440. doi: 10.1161/01.cir.71.3.434. [DOI] [PubMed] [Google Scholar]
  32. Seyberth H. W., Bonsch G., Müller H., Minne H. W., Erlenmaier T., Strein K., Imbeck H., Mrongovius R. Prostaglandin E production and hypercalcaemia in rats bearing the Walker carcinosarcoma. Br J Cancer. 1980 Sep;42(3):455–461. doi: 10.1038/bjc.1980.258. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Sladek K., Dworski R., Fitzgerald G. A., Buitkus K. L., Block F. J., Marney S. R., Jr, Sheller J. R. Allergen-stimulated release of thromboxane A2 and leukotriene E4 in humans. Effect of indomethacin. Am Rev Respir Dis. 1990 Jun;141(6):1441–1445. doi: 10.1164/ajrccm/141.6.1441. [DOI] [PubMed] [Google Scholar]
  34. Wallace J. L. Glucocorticoid-induced gastric mucosal damage: inhibition of leukotriene, but not prostaglandin biosynthesis. Prostaglandins. 1987 Aug;34(2):311–323. doi: 10.1016/0090-6980(87)90252-8. [DOI] [PubMed] [Google Scholar]
  35. Weksler B. B., Marcus A. J., Jaffe E. A. Synthesis of prostaglandin I2 (prostacyclin) by cultured human and bovine endothelial cells. Proc Natl Acad Sci U S A. 1977 Sep;74(9):3922–3926. doi: 10.1073/pnas.74.9.3922. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Williams J. D., Lee T. H., Lewis R. A., Austen F. Intracellular retention of the 5-lipoxygenase pathway product, leukotriene B4, by human neutrophils activated with unopsonized zymosan. J Immunol. 1985 Apr;134(4):2624–2630. [PubMed] [Google Scholar]
  37. Wong E., Barr R. M., Cunningham F. M., Mistry K., Woollard P. M., Mallet A. I., Greaves M. W. Topical steroid treatment reduces arachidonic acid and leukotriene B4 in lesional skin of psoriasis. Br J Clin Pharmacol. 1986 Dec;22(6):627–632. doi: 10.1111/j.1365-2125.1986.tb02949.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES