Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1989 Jun;83(6):1936–1940. doi: 10.1172/JCI114101

Inhibition of O2- generation by dexamethasone is mimicked by lipocortin I in alveolar macrophages.

I Maridonneau-Parini 1, M Errasfa 1, F Russo-Marie 1
PMCID: PMC303915  PMID: 2542378

Abstract

Glucocorticoids inhibit superoxide (O2-) generation by phagocytes through a mechanism that remains unclear. We investigated this effect by using dexamethasone on guinea pig alveolar macrophages. O2- generation was induced either by the calcium ionophore A23187, a potent stimulus of phospholipase A2, or by the protein kinase C activator, phorbol myristate acetate (PMA). Dexamethasone inhibited O2- generation initiated by A23187 by 50-55%. This inhibition required: (a) more than 45 min incubation and was maximal after 2 h; (b) glucocorticoid receptor occupancy; and (c) protein synthesis. The inhibitory effect of dexamethasone could not be explained by an interaction with the respiratory burst enzyme NADPH oxidase since O2- generation was only weakly affected upon PMA stimulation. Lipocortin I, a glucocorticoid inducible and phospholipase A2 inhibitory protein, inhibited O2- generation initiated by A23187 but failed to modulate the respiratory burst activated by PMA. These results were obtained with lipocortin I purified from mouse lungs, human blood mononuclear cells, and with human recombinant lipocortin I. We propose that lipocortin I is capable of inhibiting the activation of NADPH oxidase only when membrane signal transduction involves phospholipase A2. By mimicking the effect of dexamethasone, lipocortin I may extend its potential anti-inflammatory action to the partial control of the formation of oxygen reactive species by phagocytes.

Full text

PDF
1937

Selected References

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

  1. Blackwell G. J., Carnuccio R., Di Rosa M., Flower R. J., Parente L., Persico P. Macrocortin: a polypeptide causing the anti-phospholipase effect of glucocorticoids. Nature. 1980 Sep 11;287(5778):147–149. doi: 10.1038/287147a0. [DOI] [PubMed] [Google Scholar]
  2. Bromberg Y., Pick E. Unsaturated fatty acids as second messengers of superoxide generation by macrophages. Cell Immunol. 1983 Jul 15;79(2):240–252. doi: 10.1016/0008-8749(83)90067-9. [DOI] [PubMed] [Google Scholar]
  3. Cirino G., Flower R. J., Browning J. L., Sinclair L. K., Pepinsky R. B. Recombinant human lipocortin 1 inhibits thromboxane release from guinea-pig isolated perfused lung. Nature. 1987 Jul 16;328(6127):270–272. doi: 10.1038/328270a0. [DOI] [PubMed] [Google Scholar]
  4. Cloix J. F., Colard O., Rothhut B., Russo-Marie F. Characterization and partial purification of 'renocortins': two polypeptides formed in renal cells causing the anti-phospholipase-like action of glucocorticoids. Br J Pharmacol. 1983 May;79(1):313–321. doi: 10.1111/j.1476-5381.1983.tb10526.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. 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]
  6. Davies A. O., Lefkowitz R. J. Corticosteroid-induced differential regulation of beta-adrenergic receptors in circulating human polymorphonuclear leukocytes and mononuclear leukocytes. J Clin Endocrinol Metab. 1980 Sep;51(3):599–605. doi: 10.1210/jcem-51-3-599. [DOI] [PubMed] [Google Scholar]
  7. Emilsson A., Sundler R. Studies on the enzymatic pathways of calcium ionophore-induced phospholipid degradation and arachidonic acid mobilization in peritoneal macrophages. Biochim Biophys Acta. 1985 Aug 30;846(2):265–274. doi: 10.1016/0167-4889(85)90074-6. [DOI] [PubMed] [Google Scholar]
  8. Errasfa M., Bachelet M., Russo-Marie F. Inhibition of phospholipase A2 activity of guinea-pig alveolar macrophages by lipocortin-like proteins purified from mice lung. Biochem Biophys Res Commun. 1988 Jun 30;153(3):1267–1270. doi: 10.1016/s0006-291x(88)81364-0. [DOI] [PubMed] [Google Scholar]
  9. 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]
  10. Gerard C., McPhail L. C., Marfat A., Stimler-Gerard N. P., Bass D. A., McCall C. E. Role of protein kinases in stimulation of human polymorphonuclear leukocyte oxidative metabolism by various agonists. Differential effects of a novel protein kinase inhibitor. J Clin Invest. 1986 Jan;77(1):61–65. doi: 10.1172/JCI112302. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Grzeskowiak M., Della Bianca V., De Togni P., Papini E., Rossi F. Independence with respect to Ca2+ changes of the neutrophil respiratory and secretory response to exogenous phospholipase C and possible involvement of diacylglycerol and protein kinase C. Biochim Biophys Acta. 1985 Jan 18;844(1):81–90. doi: 10.1016/0167-4889(85)90237-x. [DOI] [PubMed] [Google Scholar]
  12. Hirata F., Schiffmann E., Venkatasubramanian K., Salomon D., Axelrod J. A phospholipase A2 inhibitory protein in rabbit neutrophils induced by glucocorticoids. Proc Natl Acad Sci U S A. 1980 May;77(5):2533–2536. doi: 10.1073/pnas.77.5.2533. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Maridonneau-Parini I., Clerc J., Polla B. S. Heat shock inhibits NADPH oxidase in human neutrophils. Biochem Biophys Res Commun. 1988 Jul 15;154(1):179–186. doi: 10.1016/0006-291x(88)90667-5. [DOI] [PubMed] [Google Scholar]
  14. Maridonneau-Parini I., Lagente V., Lefort J., Randon J., Russo-Marie F., Vargaftig B. B. Desensitization to PAF-induced bronchoconstriction and to activation of alveolar macrophages by repeated inhalations of PAF in the guinea pig. Biochem Biophys Res Commun. 1985 Aug 30;131(1):42–49. doi: 10.1016/0006-291x(85)91767-x. [DOI] [PubMed] [Google Scholar]
  15. Maridonneau-Parini I., Tauber A. I. Activation of NADPH-oxidase by arachidonic acid involves phospholipase A2 in intact human neutrophils but not in the cell-free system. Biochem Biophys Res Commun. 1986 Aug 14;138(3):1099–1105. doi: 10.1016/s0006-291x(86)80395-3. [DOI] [PubMed] [Google Scholar]
  16. Maridonneau-Parini I., Tringale S. M., Tauber A. I. Identification of distinct activation pathways of the human neutrophil NADPH-oxidase. J Immunol. 1986 Nov 1;137(9):2925–2929. [PubMed] [Google Scholar]
  17. Northup J. K., Valentine-Braun K. A., Johnson L. K., Severson D. L., Hollenberg M. D. Evaluation of the antiinflammatory and phospholipase-inhibitory activity of calpactin II/lipocortin I. J Clin Invest. 1988 Oct;82(4):1347–1352. doi: 10.1172/JCI113737. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Pepinsky R. B., Tizard R., Mattaliano R. J., Sinclair L. K., Miller G. T., Browning J. L., Chow E. P., Burne C., Huang K. S., Pratt D. Five distinct calcium and phospholipid binding proteins share homology with lipocortin I. J Biol Chem. 1988 Aug 5;263(22):10799–10811. [PubMed] [Google Scholar]
  19. 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]
  20. Petroni K. C., Shen L., Guyre P. M. Modulation of human polymorphonuclear leukocyte IgG Fc receptors and Fc receptor-mediated functions by IFN-gamma and glucocorticoids. J Immunol. 1988 May 15;140(10):3467–3472. [PubMed] [Google Scholar]
  21. Rothhut B., Comera C., Prieur B., Errasfa M., Minassian G., Russo-Marie F. Purification and characterization of a 32-kDa phospholipase A2 inhibitory protein (lipocortin) from human peripheral blood mononuclear cells. FEBS Lett. 1987 Jul 13;219(1):169–175. doi: 10.1016/0014-5793(87)81211-5. [DOI] [PubMed] [Google Scholar]
  22. Rothhut B., Russo-Marie F., Wood J., DiRosa M., Flower R. J. Further characterization of the glucocorticoid-induced antiphospholipase protein "renocortin". Biochem Biophys Res Commun. 1983 Dec 28;117(3):878–884. doi: 10.1016/0006-291x(83)91678-9. [DOI] [PubMed] [Google Scholar]
  23. 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]
  24. Sakata A., Ida E., Tominaga M., Onoue K. Arachidonic acid acts as an intracellular activator of NADPH-oxidase in Fc gamma receptor-mediated superoxide generation in macrophages. J Immunol. 1987 Jun 15;138(12):4353–4359. [PubMed] [Google Scholar]
  25. Serhan C. N., Broekman M. J., Korchak H. M., Smolen J. E., Marcus A. J., Weissmann G. Changes in phosphatidylinositol and phosphatidic acid in stimulated human neutrophils. Relationship to calcium mobilization, aggregation and superoxide radical generation. Biochim Biophys Acta. 1983 Jun 2;762(3):420–428. doi: 10.1016/0167-4889(83)90007-1. [DOI] [PubMed] [Google Scholar]
  26. Shaw J. O., Klusick S. J., Hanahan D. J. Activation of rabbit platelet phospholipase and thromboxane synthesis by 1-O-hexadecyl/octadecyl-2-acetyl-sn-glyceryl-3-phosphorylcholine (platelet activating factor). Biochim Biophys Acta. 1981 Jan 26;663(1):222–229. doi: 10.1016/0005-2760(81)90208-3. [DOI] [PubMed] [Google Scholar]
  27. Smolen J. E., Weissmann G. Effects of indomethacin, 5,8,11,14-eicosatetraynoic acid, and p-bromophenacyl bromide on lysosomal enzyme release and superoxide anion generation by human polymorphonuclear leukocytes. Biochem Pharmacol. 1980 Feb 15;29(4):533–538. doi: 10.1016/0006-2952(80)90373-1. [DOI] [PubMed] [Google Scholar]
  28. Tauber A. I. Protein kinase C and the activation of the human neutrophil NADPH-oxidase. Blood. 1987 Mar;69(3):711–720. [PubMed] [Google Scholar]
  29. Towbin H., Staehelin T., Gordon J. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci U S A. 1979 Sep;76(9):4350–4354. doi: 10.1073/pnas.76.9.4350. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Walsh C. E., Waite B. M., Thomas M. J., DeChatelet L. R. Release and metabolism of arachidonic acid in human neutrophils. J Biol Chem. 1981 Jul 25;256(14):7228–7234. [PubMed] [Google Scholar]
  31. Webb D. S., Roth J. A. Relationship of glucocorticoid suppression of arachidonic acid metabolism to alteration of neutrophil function. J Leukoc Biol. 1987 Feb;41(2):156–164. doi: 10.1002/jlb.41.2.156. [DOI] [PubMed] [Google Scholar]
  32. Yodoi J., Hirashima M., Ishizaka K. Lymphocytes bearing Fc receptors for IgE. VI. Suppressive effect of glucocorticoids on the expression of Fc epsilon receptors and glycosylation of IgE-binding factors. J Immunol. 1981 Aug;127(2):471–476. [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES