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 Apr;87(7):2838–2842. doi: 10.1073/pnas.87.7.2838

Glucocorticoid up-regulation of high-affinity interleukin 6 receptors on human epithelial cells.

L Snyers 1, L De Wit 1, J Content 1
PMCID: PMC53786  PMID: 2157217

Abstract

Interleukin 6 (IL-6) is a potent pleiotropic cytokine, known, among others, to stimulate immunoglobulin production by B cells and to trigger acute-phase protein synthesis by hepatocytes. Similar to IL-1, it is produced by monocytes and macrophages following an inflammatory challenge. Analysis of IL-6 receptor (IL-6R) expression on different human cell lines indicates that dexamethasone could up-regulate the number of IL-6R on one epithelial cell line (UAC) and on two hepatoma cell lines (HepG2 and Hep3B). This effect was confirmed by Scatchard analysis of binding experiments, using [35S]methionine and [35S]cysteine metabolically labeled IL-6. It was confirmed at the level of mRNA expression by Northern blot analysis. These results provide evidence for a link between IL-6 and glucocorticoids. They could represent an example of a system in which one role of glucocorticoids is to define more accurately the target of cytokines, and they could explain, at least partly, the frequently observed synergy between IL-6 and glucocorticoids, notably in the case of hepatocytes.

Full text

PDF
2838

Images in this article

2841Image
on p.2841
2841Image
on p.2841
2841Image
on p.2841

Selected References

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

  1. Akahoshi T., Oppenheim J. J., Matsushima K. Induction of high-affinity interleukin 1 receptor on human peripheral blood lymphocytes by glucocorticoid hormones. J Exp Med. 1988 Mar 1;167(3):924–936. doi: 10.1084/jem.167.3.924. [DOI] [PMC free article] [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. Bauer J., Lengyel G., Bauer T. M., Acs G., Gerok W. Regulation of interleukin-6 receptor expression in human monocytes and hepatocytes. FEBS Lett. 1989 May 22;249(1):27–30. doi: 10.1016/0014-5793(89)80008-0. [DOI] [PubMed] [Google Scholar]
  4. Baumann H., Richards C., Gauldie J. Interaction among hepatocyte-stimulating factors, interleukin 1, and glucocorticoids for regulation of acute phase plasma proteins in human hepatoma (HepG2) cells. J Immunol. 1987 Dec 15;139(12):4122–4128. [PubMed] [Google Scholar]
  5. Bernton E. W., Beach J. E., Holaday J. W., Smallridge R. C., Fein H. G. Release of multiple hormones by a direct action of interleukin-1 on pituitary cells. Science. 1987 Oct 23;238(4826):519–521. doi: 10.1126/science.2821620. [DOI] [PubMed] [Google Scholar]
  6. Blalock J. E., Smith E. M. Human leukocyte interferon: structural and biological relatedness to adrenocorticotropic hormone and endorphins. Proc Natl Acad Sci U S A. 1980 Oct;77(10):5972–5974. doi: 10.1073/pnas.77.10.5972. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Content J., De Wit L., Poupart P., Opdenakker G., Van Damme J., Billiau A. Induction of a 26-kDa-protein mRNA in human cells treated with an interleukin-1-related, leukocyte-derived factor. Eur J Biochem. 1985 Oct 15;152(2):253–257. doi: 10.1111/j.1432-1033.1985.tb09191.x. [DOI] [PubMed] [Google Scholar]
  8. Coulie P. G., Vanhecke A., Van Damme J., Cayphas S., Poupart P., De Wit L., Content J. High-affinity binding sites for human 26-kDa protein (interleukin 6, B cell stimulatory factor-2, human hybridoma plasmacytoma growth factor, interferon-beta 2), different from those of type I interferon (alpha, beta), on lymphoblastoid cells. Eur J Immunol. 1987 Oct;17(10):1435–1440. doi: 10.1002/eji.1830171008. [DOI] [PubMed] [Google Scholar]
  9. Deviere J., Content J., Denys C., Vandenbussche P., Schandene L., Wybran J., Dupont E. High interleukin-6 serum levels and increased production by leucocytes in alcoholic liver cirrhosis. Correlation with IgA serum levels and lymphokines production. Clin Exp Immunol. 1989 Aug;77(2):221–225. [PMC free article] [PubMed] [Google Scholar]
  10. Emilie D., Crevon M. C., Auffredou M. T., Galanaud P. Glucocorticosteroid-dependent synergy between interleukin 1 and interleukin 6 for human B lymphocyte differentiation. Eur J Immunol. 1988 Dec;18(12):2043–2047. doi: 10.1002/eji.1830181226. [DOI] [PubMed] [Google Scholar]
  11. Fan C. M., Maniatis T. Two different virus-inducible elements are required for human beta-interferon gene regulation. EMBO J. 1989 Jan;8(1):101–110. doi: 10.1002/j.1460-2075.1989.tb03353.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Farrar W. L., Ferris D. K., Harel-Bellan A. The molecular basis of immune cytokine action. Crit Rev Ther Drug Carrier Syst. 1989;5(4):229–261. [PubMed] [Google Scholar]
  13. Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
  14. Gauldie J., Richards C., Harnish D., Lansdorp P., Baumann H. Interferon beta 2/B-cell stimulatory factor type 2 shares identity with monocyte-derived hepatocyte-stimulating factor and regulates the major acute phase protein response in liver cells. Proc Natl Acad Sci U S A. 1987 Oct;84(20):7251–7255. doi: 10.1073/pnas.84.20.7251. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gessani S., McCandless S., Baglioni C. The glucocorticoid dexamethasone inhibits synthesis of interferon by decreasing the level of its mRNA. J Biol Chem. 1988 Jun 5;263(16):7454–7457. [PubMed] [Google Scholar]
  16. Green A. R. Peptide regulatory factors: multifunctional mediators of cellular growth and differentiation. Lancet. 1989 Apr 1;1(8640):705–707. doi: 10.1016/s0140-6736(89)92216-2. [DOI] [PubMed] [Google Scholar]
  17. Hatakeyama M., Tsudo M., Minamoto S., Kono T., Doi T., Miyata T., Miyasaka M., Taniguchi T. Interleukin-2 receptor beta chain gene: generation of three receptor forms by cloned human alpha and beta chain cDNA's. Science. 1989 May 5;244(4904):551–556. doi: 10.1126/science.2785715. [DOI] [PubMed] [Google Scholar]
  18. Kohase M., Henriksen-Destefano D., Sehgal P. B., Vilcek J. Dexamethasone inhibits feedback regulation of the mitogenic activity of tumor necrosis factor, interleukin-1, and epidermal growth factor in human fibroblasts. J Cell Physiol. 1987 Aug;132(2):271–278. doi: 10.1002/jcp.1041320211. [DOI] [PubMed] [Google Scholar]
  19. Kull F. C., Jr Reduction in tumor necrosis factor receptor affinity and cytotoxicity by glucocorticoids. Biochem Biophys Res Commun. 1988 May 31;153(1):402–409. doi: 10.1016/s0006-291x(88)81238-5. [DOI] [PubMed] [Google Scholar]
  20. Le J. M., Fredrickson G., Reis L. F., Diamantstein T., Hirano T., Kishimoto T., Vilcek J. Interleukin 2-dependent and interleukin 2-independent pathways of regulation of thymocyte function by interleukin 6. Proc Natl Acad Sci U S A. 1988 Nov;85(22):8643–8647. doi: 10.1073/pnas.85.22.8643. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Morrone G., Ciliberto G., Oliviero S., Arcone R., Dente L., Content J., Cortese R. Recombinant interleukin 6 regulates the transcriptional activation of a set of human acute phase genes. J Biol Chem. 1988 Sep 5;263(25):12554–12558. [PubMed] [Google Scholar]
  22. Naitoh Y., Fukata J., Tominaga T., Nakai Y., Tamai S., Mori K., Imura H. Interleukin-6 stimulates the secretion of adrenocorticotropic hormone in conscious, freely-moving rats. Biochem Biophys Res Commun. 1988 Sep 30;155(3):1459–1463. doi: 10.1016/s0006-291x(88)81305-6. [DOI] [PubMed] [Google Scholar]
  23. Nishida T., Nakai S., Kawakami T., Aihara K., Nishino N., Hirai Y. Dexamethasone regulation of the expression of cytokine mRNAs induced by interleukin-1 in the astrocytoma cell line U373MG. FEBS Lett. 1989 Jan 16;243(1):25–29. doi: 10.1016/0014-5793(89)81210-4. [DOI] [PubMed] [Google Scholar]
  24. Noma T., Mizuta T., Rosén A., Hirano T., Kishimoto T., Honjo T. Enhancement of the interleukin 2 receptor expression on T cells by multiple B-lymphotropic lymphokines. Immunol Lett. 1987 Jul;15(3):249–253. doi: 10.1016/0165-2478(87)90032-0. [DOI] [PubMed] [Google Scholar]
  25. Otto J. M., Grenett H. E., Fuller G. M. The coordinated regulation of fibrinogen gene transcription by hepatocyte-stimulating factor and dexamethasone. J Cell Biol. 1987 Sep;105(3):1067–1072. doi: 10.1083/jcb.105.3.1067. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Poupart P., Vandenabeele P., Cayphas S., Van Snick J., Haegeman G., Kruys V., Fiers W., Content J. B cell growth modulating and differentiating activity of recombinant human 26-kd protein (BSF-2, HuIFN-beta 2, HPGF). EMBO J. 1987 May;6(5):1219–1224. doi: 10.1002/j.1460-2075.1987.tb02357.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Sapolsky R., Rivier C., Yamamoto G., Plotsky P., Vale W. Interleukin-1 stimulates the secretion of hypothalamic corticotropin-releasing factor. Science. 1987 Oct 23;238(4826):522–524. doi: 10.1126/science.2821621. [DOI] [PubMed] [Google Scholar]
  28. Snyder D. S., Unanue E. R. Corticosteroids inhibit murine macrophage Ia expression and interleukin 1 production. J Immunol. 1982 Nov;129(5):1803–1805. [PubMed] [Google Scholar]
  29. Snyers L., Fontaine V., Content J. Modulation of interleukin-6 receptors in human cells. Ann N Y Acad Sci. 1989;557:388–395. doi: 10.1111/j.1749-6632.1989.tb24031.x. [DOI] [PubMed] [Google Scholar]
  30. Sporn M. B., Roberts A. B. Peptide growth factors are multifunctional. Nature. 1988 Mar 17;332(6161):217–219. doi: 10.1038/332217a0. [DOI] [PubMed] [Google Scholar]
  31. Sternberg E. M., Hill J. M., Chrousos G. P., Kamilaris T., Listwak S. J., Gold P. W., Wilder R. L. Inflammatory mediator-induced hypothalamic-pituitary-adrenal axis activation is defective in streptococcal cell wall arthritis-susceptible Lewis rats. Proc Natl Acad Sci U S A. 1989 Apr;86(7):2374–2378. doi: 10.1073/pnas.86.7.2374. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Strickland R. W., Wahl L. M., Finbloom D. S. Corticosteroids enhance the binding of recombinant interferon-gamma to cultured human monocytes. J Immunol. 1986 Sep 1;137(5):1577–1580. [PubMed] [Google Scholar]
  33. Taga T., Hibi M., Hirata Y., Yamasaki K., Yasukawa K., Matsuda T., Hirano T., Kishimoto T. Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130. Cell. 1989 Aug 11;58(3):573–581. doi: 10.1016/0092-8674(89)90438-8. [DOI] [PubMed] [Google Scholar]
  34. Taga T., Kawanishi Y., Hardy R. R., Hirano T., Kishimoto T. Receptors for B cell stimulatory factor 2. Quantitation, specificity, distribution, and regulation of their expression. J Exp Med. 1987 Oct 1;166(4):967–981. doi: 10.1084/jem.166.4.967. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Taniguchi T. Regulation of cytokine gene expression. Annu Rev Immunol. 1988;6:439–464. doi: 10.1146/annurev.iy.06.040188.002255. [DOI] [PubMed] [Google Scholar]
  36. Taylor A. L., Fishman L. M. Corticotropin-releasing hormone. N Engl J Med. 1988 Jul 28;319(4):213–222. doi: 10.1056/NEJM198807283190405. [DOI] [PubMed] [Google Scholar]
  37. Vankelecom H., Carmeliet P., Van Damme J., Billiau A., Denef C. Production of interleukin-6 by folliculo-stellate cells of the anterior pituitary gland in a histiotypic cell aggregate culture system. Neuroendocrinology. 1989 Jan;49(1):102–106. doi: 10.1159/000125097. [DOI] [PubMed] [Google Scholar]
  38. Waage A., Bakke O. Glucocorticoids suppress the production of tumour necrosis factor by lipopolysaccharide-stimulated human monocytes. Immunology. 1988 Feb;63(2):299–302. [PMC free article] [PubMed] [Google Scholar]
  39. Woloski B. M., Smith E. M., Meyer W. J., 3rd, Fuller G. M., Blalock J. E. Corticotropin-releasing activity of monokines. Science. 1985 Nov 29;230(4729):1035–1037. doi: 10.1126/science.2997929. [DOI] [PubMed] [Google Scholar]
  40. Yamasaki K., Taga T., Hirata Y., Yawata H., Kawanishi Y., Seed B., Taniguchi T., Hirano T., Kishimoto T. Cloning and expression of the human interleukin-6 (BSF-2/IFN beta 2) receptor. Science. 1988 Aug 12;241(4867):825–828. doi: 10.1126/science.3136546. [DOI] [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