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The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1991 May;87(5):1739–1747. doi: 10.1172/JCI115192

Dexamethasone inhibits human interleukin 2 but not interleukin 2 receptor gene expression in vitro at the level of nuclear transcription.

D T Boumpas 1, E D Anastassiou 1, S A Older 1, G C Tsokos 1, D L Nelson 1, J E Balow 1
PMCID: PMC295281  PMID: 2022743

Abstract

Glucocorticosteroids have an inhibitory effect on the expression of interleukin 2 (IL-2) and interleukin 2 receptor (IL-2R) genes. To determine the mechanisms of this inhibition, human T lymphocytes were stimulated with mitogens in the presence of dexamethasone. Nuclear transcription run-off assays showed that high doses of dexamethasone inhibited the transcription of the IL-2 gene but not that of the IL-2R gene. Post-transcriptionally, high doses of dexamethasone (10(-4) M) were required to inhibit IL-2R mRNA levels by 50%, whereas lower doses (10(-6) M) inhibited by greater than 70% the accumulation of IL-2 mRNA. IL-2 mRNA half-life decreased in the presence of dexamethasone (10(-6) M) by approximately 50%. At the protein product level, dexamethasone inhibited both IL-2 production, as well as cell surface and soluble forms of IL-2R. IL-2R gene expression was inhibited for at least 72 h after exposure of cells to dexamethasone. In the presence of exogenous IL-2, dexamethasone failed to exert a significant effect on the production of IL-2R protein. These data indicate that dexamethasone has a greater effect on the expression of the IL-2 gene than on the IL-2R gene. Dexamethasone both inhibits transcription of the IL-2 gene and decreases the stability of IL-2 mRNA. The effect of dexamethasone on the IL-2R gene is post-transcriptional and may result indirectly from decreased IL-2 production.

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Selected References

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  1. Ali M., Vedeckis W. V. The glucocorticoid receptor protein binds to transfer RNA. Science. 1987 Jan 23;235(4787):467–470. doi: 10.1126/science.3798121. [DOI] [PubMed] [Google Scholar]
  2. Arya S. K., Wong-Staal F., Gallo R. C. Dexamethasone-mediated inhibition of human T cell growth factor and gamma-interferon messenger RNA. J Immunol. 1984 Jul;133(1):273–276. [PubMed] [Google Scholar]
  3. Axelrod L. Glucocorticoid therapy. Medicine (Baltimore) 1976 Jan;55(1):39–65. doi: 10.1097/00005792-197601000-00003. [DOI] [PubMed] [Google Scholar]
  4. Beato M. Gene regulation by steroid hormones. Cell. 1989 Feb 10;56(3):335–344. doi: 10.1016/0092-8674(89)90237-7. [DOI] [PubMed] [Google Scholar]
  5. Bettens F., Kristensen F., Walker C., Schwuléra U., Bonnard G. D., de Weck A. L. Lymphokine regulation of activated (G1) lymphocytes. II. Glucocorticoid and anti-Tac-induced inhibition of human T lymphocyte proliferation. J Immunol. 1984 Jan;132(1):261–265. [PubMed] [Google Scholar]
  6. Bickel M., Cohen R. B., Pluznik D. H. Post-transcriptional regulation of granulocyte-macrophage colony-stimulating factor synthesis in murine T cells. J Immunol. 1990 Aug 1;145(3):840–845. [PubMed] [Google Scholar]
  7. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  8. Cross S. L., Feinberg M. B., Wolf J. B., Holbrook N. J., Wong-Staal F., Leonard W. J. Regulation of the human interleukin-2 receptor alpha chain promoter: activation of a nonfunctional promoter by the transactivator gene of HTLV-I. Cell. 1987 Apr 10;49(1):47–56. doi: 10.1016/0092-8674(87)90754-9. [DOI] [PubMed] [Google Scholar]
  9. Dennis G., June C. H., Mizuguchi J., Ohara J., Witherspoon K., Finkelman F. D., McMillan V., Mond J. J. Glucocorticoids suppress calcium mobilization and phospholipid hydrolysis in anti-Ig antibody-stimulated B cells. J Immunol. 1987 Oct 15;139(8):2516–2523. [PubMed] [Google Scholar]
  10. Depper J. M., Leonard W. J., Drogula C., Krönke M., Waldmann T. A., Greene W. C. Interleukin 2 (IL-2) augments transcription of the IL-2 receptor gene. Proc Natl Acad Sci U S A. 1985 Jun;82(12):4230–4234. doi: 10.1073/pnas.82.12.4230. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Dony C., Kessel M., Gruss P. Post-transcriptional control of myc and p53 expression during differentiation of the embryonal carcinoma cell line F9. Nature. 1985 Oct 17;317(6038):636–639. doi: 10.1038/317636a0. [DOI] [PubMed] [Google Scholar]
  12. Durand D. B., Bush M. R., Morgan J. G., Weiss A., Crabtree G. R. A 275 basepair fragment at the 5' end of the interleukin 2 gene enhances expression from a heterologous promoter in response to signals from the T cell antigen receptor. J Exp Med. 1987 Feb 1;165(2):395–407. doi: 10.1084/jem.165.2.395. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Efrat S., Kaempfer R. Control of biologically active interleukin 2 messenger RNA formation in induced human lymphocytes. Proc Natl Acad Sci U S A. 1984 May;81(9):2601–2605. doi: 10.1073/pnas.81.9.2601. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Fujita T., Shibuya H., Ohashi T., Yamanishi K., Taniguchi T. Regulation of human interleukin-2 gene: functional DNA sequences in the 5' flanking region for the gene expression in activated T lymphocytes. Cell. 1986 Aug 1;46(3):401–405. doi: 10.1016/0092-8674(86)90660-4. [DOI] [PubMed] [Google Scholar]
  15. Gillis S., Crabtree G. R., Smith K. A. Glucocorticoid-induced inhibition of T cell growth factor production. I. The effect on mitogen-induced lymphocyte proliferation. J Immunol. 1979 Oct;123(4):1624–1631. [PubMed] [Google Scholar]
  16. Kelly K., Siebenlist U. Mitogenic activation of normal T cells leads to increased initiation of transcription in the c-myc locus. J Biol Chem. 1988 Apr 5;263(10):4828–4831. [PubMed] [Google Scholar]
  17. Kern J. A., Lamb R. J., Reed J. C., Daniele R. P., Nowell P. C. Dexamethasone inhibition of interleukin 1 beta production by human monocytes. Posttranscriptional mechanisms. J Clin Invest. 1988 Jan;81(1):237–244. doi: 10.1172/JCI113301. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kroemer G., Wick G. The role of interleukin 2 in autoimmunity. Immunol Today. 1989 Jul;10(7):246–251. doi: 10.1016/0167-5699(89)90262-4. [DOI] [PubMed] [Google Scholar]
  19. Krönke M., Leonard W. J., Depper J. M., Arya S. K., Wong-Staal F., Gallo R. C., Waldmann T. A., Greene W. C. Cyclosporin A inhibits T-cell growth factor gene expression at the level of mRNA transcription. Proc Natl Acad Sci U S A. 1984 Aug;81(16):5214–5218. doi: 10.1073/pnas.81.16.5214. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Krönke M., Leonard W. J., Depper J. M., Greene W. C. Sequential expression of genes involved in human T lymphocyte growth and differentiation. J Exp Med. 1985 Jun 1;161(6):1593–1598. doi: 10.1084/jem.161.6.1593. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Leonard W. J., Krönke M., Peffer N. J., Depper J. M., Greene W. C. Interleukin 2 receptor gene expression in normal human T lymphocytes. Proc Natl Acad Sci U S A. 1985 Sep;82(18):6281–6285. doi: 10.1073/pnas.82.18.6281. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Leonard W. J., Krönke M., Peffer N. J., Depper J. M., Greene W. C. Interleukin 2 receptor gene expression in normal human T lymphocytes. Proc Natl Acad Sci U S A. 1985 Sep;82(18):6281–6285. doi: 10.1073/pnas.82.18.6281. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Lindstein T., June C. H., Ledbetter J. A., Stella G., Thompson C. B. Regulation of lymphokine messenger RNA stability by a surface-mediated T cell activation pathway. Science. 1989 Apr 21;244(4902):339–343. doi: 10.1126/science.2540528. [DOI] [PubMed] [Google Scholar]
  24. Piechaczyk M., Blanchard J. M., Marty L., Dani C., Panabieres F., El Sabouty S., Fort P., Jeanteur P. Post-transcriptional regulation of glyceraldehyde-3-phosphate-dehydrogenase gene expression in rat tissues. Nucleic Acids Res. 1984 Sep 25;12(18):6951–6963. doi: 10.1093/nar/12.18.6951. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Pomerantz J. L., Mauxion F., Yoshida M., Greene W. C., Sen R. A second sequence element located 3' to the NF-kappa B-binding site regulates IL-2 receptor-alpha gene induction. J Immunol. 1989 Dec 15;143(12):4275–4281. [PubMed] [Google Scholar]
  26. Redondo J. M., Fresno M., López-Rivas A. Inhibition of interleukin 2-induced proliferation of cloned murine T cells by glucocorticoids. Possible involvement of an inhibitory protein. Eur J Immunol. 1988 Oct;18(10):1555–1559. doi: 10.1002/eji.1830181013. [DOI] [PubMed] [Google Scholar]
  27. Reed J. C., Abidi A. H., Alpers J. D., Hoover R. G., Robb R. J., Nowell P. C. Effect of cyclosporin A and dexamethasone on interleukin 2 receptor gene expression. J Immunol. 1986 Jul 1;137(1):150–154. [PubMed] [Google Scholar]
  28. Reed J. C., Sabath D. E., Hoover R. G., Prystowsky M. B. Recombinant interleukin 2 regulates levels of c-myc mRNA in a cloned murine T lymphocyte. Mol Cell Biol. 1985 Dec;5(12):3361–3368. doi: 10.1128/mcb.5.12.3361. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Ringold G. M. Steroid hormone regulation of gene expression. Annu Rev Pharmacol Toxicol. 1985;25:529–566. doi: 10.1146/annurev.pa.25.040185.002525. [DOI] [PubMed] [Google Scholar]
  30. Robins D. M., Schimke R. T. Differential effects of estrogen and progesterone on ovalbumin mRNA utilization. J Biol Chem. 1978 Dec 25;253(24):8925–8934. [PubMed] [Google Scholar]
  31. Rubin L. A., Kurman C. C., Fritz M. E., Biddison W. E., Boutin B., Yarchoan R., Nelson D. L. Soluble interleukin 2 receptors are released from activated human lymphoid cells in vitro. J Immunol. 1985 Nov;135(5):3172–3177. [PubMed] [Google Scholar]
  32. Shaw G., Kamen R. A conserved AU sequence from the 3' untranslated region of GM-CSF mRNA mediates selective mRNA degradation. Cell. 1986 Aug 29;46(5):659–667. doi: 10.1016/0092-8674(86)90341-7. [DOI] [PubMed] [Google Scholar]
  33. Shaw J. P., Utz P. J., Durand D. B., Toole J. J., Emmel E. A., Crabtree G. R. Identification of a putative regulator of early T cell activation genes. Science. 1988 Jul 8;241(4862):202–205. doi: 10.1126/science.3260404. [DOI] [PubMed] [Google Scholar]
  34. Shaw J., Meerovitch K., Bleackley R. C., Paetkau V. Mechanisms regulating the level of IL-2 mRNA in T lymphocytes. J Immunol. 1988 Apr 1;140(7):2243–2248. [PubMed] [Google Scholar]
  35. Shaw J., Meerovitch K., Elliott J. F., Bleackley R. C., Paetkau V. Induction, suppression and superinduction of lymphokine mRNA in T lymphocytes. Mol Immunol. 1987 May;24(5):409–419. doi: 10.1016/0161-5890(87)90014-9. [DOI] [PubMed] [Google Scholar]
  36. Smith K. A., Cantrell D. A. Interleukin 2 regulates its own receptors. Proc Natl Acad Sci U S A. 1985 Feb;82(3):864–868. doi: 10.1073/pnas.82.3.864. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Waldmann T. A. The structure, function, and expression of interleukin-2 receptors on normal and malignant lymphocytes. Science. 1986 May 9;232(4751):727–732. doi: 10.1126/science.3008337. [DOI] [PubMed] [Google Scholar]
  38. Weiss A., Imboden J., Hardy K., Manger B., Terhorst C., Stobo J. The role of the T3/antigen receptor complex in T-cell activation. Annu Rev Immunol. 1986;4:593–619. doi: 10.1146/annurev.iy.04.040186.003113. [DOI] [PubMed] [Google Scholar]
  39. Young H. A., Birchenall-Sparks M., Kovacs E., Dorman L., Ruscetti F. W. Characterization of interleukin 2 and phorbol myristate acetate augmentation of expression of transfected human interferon-gamma genomic DNA. J Interferon Res. 1988 Aug;8(4):527–538. doi: 10.1089/jir.1988.8.527. [DOI] [PubMed] [Google Scholar]

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