Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1996 Jul 1;98(1):142–147. doi: 10.1172/JCI118759

A novel mechanism of glucocorticoid-induced immune suppression: the inhibiton of T cell-mediated terminal maturation of a murine dendritic cell line.

T Kitajima 1, K Ariizumi 1, P R Bergstresser 1, A Takashima 1
PMCID: PMC507410  PMID: 8690786

Abstract

Working with the murine epidermal-derived dendritic cell (DC) line XS52, we have observed previously that antigen-specific interaction with T cells stimulates their "terminal maturation" into fully professional DC. In this study we examined the impact of dexamethasone (DEX) on this T cell-induced event. When added to cocultures of XS52 DC and the KLH-specific Th1 clone HDK-1 in the presence of antigen, DEX at relatively low concentrations (10(-9)-10(-7) M) prevented substantially or completely each of the changes that typify terminal maturation, including (a) secretion of relatively large amounts of IL-1beta, IL-6, and TNFalpha; (b) loss of CD115 (colony-stimulating factor-1 receptor) expression and proliferative responsiveness to colony-stimulating factor-1; and (c) elevated expression of CD86 (B7-2). XS52 cells also underwent terminal maturation upon exposure to lipopolysaccharide alone, and DEX also inhibited effectively each of the same changes, indicating that DC can serve as the direct target of DEX. By contrast, DEX inhibited XS52 DC-stimulated IL-2 secretion by HDK-1 T cells, but not other changes that accompany T cell activation, including the secretion of IFNgamma and TNFalpha and the elevated expression of CD25, CD28, and CD44. These results reveal a new immunosuppressive mechanism of glucocorticoid action, that is, direct inhibition of T cell-mediated terminal maturation by DC.

Full Text

The Full Text of this article is available as a PDF (179.6 KB).

Selected References

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

  1. Amano Y., Lee S. W., Allison A. C. Inhibition by glucocorticoids of the formation of interleukin-1 alpha, interleukin-1 beta, and interleukin-6: mediation by decreased mRNA stability. Mol Pharmacol. 1993 Feb;43(2):176–182. [PubMed] [Google Scholar]
  2. Ariizumi K., Kitajima T., Bergstresser O. R., Takashima A. Interleukin-1 beta converting enzyme in murine Langerhans cells and epidermal-derived dendritic cell lines. Eur J Immunol. 1995 Aug;25(8):2137–2141. doi: 10.1002/eji.1830250803. [DOI] [PubMed] [Google Scholar]
  3. 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]
  4. Beutler B., Krochin N., Milsark I. W., Luedke C., Cerami A. Control of cachectin (tumor necrosis factor) synthesis: mechanisms of endotoxin resistance. Science. 1986 May 23;232(4753):977–980. doi: 10.1126/science.3754653. [DOI] [PubMed] [Google Scholar]
  5. Bloemena E., Van Oers M. H., Weinreich S., Schellekens P. T. Cyclosporin A and prednisolone do not inhibit the expression of high-affinity receptors for interleukin 2. Clin Exp Immunol. 1988 Feb;71(2):308–313. [PMC free article] [PubMed] [Google Scholar]
  6. Boumpas D. T., Paliogianni F., Anastassiou E. D., Balow J. E. Glucocorticosteroid action on the immune system: molecular and cellular aspects. Clin Exp Rheumatol. 1991 Jul-Aug;9(4):413–423. [PubMed] [Google Scholar]
  7. Caceres-Dittmar G., Ariizumi K., Xu S., Tapia F. J., Bergstresser P. R., Takashima A. Hydrogen peroxide mediates UV-induced impairment of antigen presentation in a murine epidermal-derived dendritic cell line. Photochem Photobiol. 1995 Jul;62(1):176–183. doi: 10.1111/j.1751-1097.1995.tb05255.x. [DOI] [PubMed] [Google Scholar]
  8. Collart M. A., Belin D., Vassalli J. D., Vassalli P. Modulations of functional activity in differentiated macrophages are accompanied by early and transient increase or decrease in c-fos gene transcription. J Immunol. 1987 Aug 1;139(3):949–955. [PubMed] [Google Scholar]
  9. Fernández-Ruiz E., Rebollo A., Nieto M. A., Sanz E., Somoza C., Ramirez F., Lopez-Rivas A., Silva A. IL-2 protects T cell hybrids from the cytolytic effect of glucocorticoids. Synergistic effect of IL-2 and dexamethasone in the induction of high-affinity IL-2 receptors. J Immunol. 1989 Dec 15;143(12):4146–4151. [PubMed] [Google Scholar]
  10. Furue M., Ishibashi Y. Differential regulation by dexamethasone and cyclosporine of human T cells activated by various stimuli. Transplantation. 1991 Sep;52(3):522–526. doi: 10.1097/00007890-199109000-00027. [DOI] [PubMed] [Google Scholar]
  11. Furue M., Katz S. I. Direct effects of glucocorticosteroids on epidermal Langerhans cells. J Invest Dermatol. 1989 Mar;92(3):342–347. doi: 10.1111/1523-1747.ep12277165. [DOI] [PubMed] [Google Scholar]
  12. Furue M., Kawakami Y., Kawakami T., Katz S. I. Differential inhibition of the T cell activation pathway by dexamethasone and cyclosporine. Transplantation. 1990 Mar;49(3):560–564. doi: 10.1097/00007890-199003000-00017. [DOI] [PubMed] [Google Scholar]
  13. Hurme M., Siljander P., Anttila H. Regulation of interleukin-1 beta production by glucocorticoids in human monocytes: the mechanism of action depends on the activation signal. Biochem Biophys Res Commun. 1991 Nov 14;180(3):1383–1389. doi: 10.1016/s0006-291x(05)81349-x. [DOI] [PubMed] [Google Scholar]
  14. Inaba K., Witmer-Pack M., Inaba M., Hathcock K. S., Sakuta H., Azuma M., Yagita H., Okumura K., Linsley P. S., Ikehara S. The tissue distribution of the B7-2 costimulator in mice: abundant expression on dendritic cells in situ and during maturation in vitro. J Exp Med. 1994 Nov 1;180(5):1849–1860. doi: 10.1084/jem.180.5.1849. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. June C. H., Bluestone J. A., Nadler L. M., Thompson C. B. The B7 and CD28 receptor families. Immunol Today. 1994 Jul;15(7):321–331. doi: 10.1016/0167-5699(94)90080-9. [DOI] [PubMed] [Google Scholar]
  16. Kawamura T., Furue M. Comparative analysis of B7-1 and B7-2 expression in Langerhans cells: differential regulation by T helper type 1 and T helper type 2 cytokines. Eur J Immunol. 1995 Jul;25(7):1913–1917. doi: 10.1002/eji.1830250718. [DOI] [PubMed] [Google Scholar]
  17. Kitajima T., Ariizumi K., Bergstresser P. R., Takashima A. T cell-dependent loss of proliferative responsiveness to colony-stimulating factor-1 by a murine epidermal-derived dendritic cell line, XS52. J Immunol. 1995 Dec 1;155(11):5190–5197. [PubMed] [Google Scholar]
  18. Kitajima T., Ariizumi K., Mohamadazadeh M., Edelbaum D., Bergstresser P. R., Takashima A. T cell-dependent secretion of IL-1 beta by a dendritic cell line (XS52) derived from murine epidermis. J Immunol. 1995 Oct 15;155(8):3794–3800. [PubMed] [Google Scholar]
  19. Knudsen P. J., Dinarello C. A., Strom T. B. Glucocorticoids inhibit transcriptional and post-transcriptional expression of interleukin 1 in U937 cells. J Immunol. 1987 Dec 15;139(12):4129–4134. [PubMed] [Google Scholar]
  20. Lamas M., Sanz E., Martin-Parras L., Espel E., Sperisen P., Collins M., Silva A. G. Glucocorticoid hormones upregulate interleukin 2 receptor alpha gene expression. Cell Immunol. 1993 Oct 15;151(2):437–450. doi: 10.1006/cimm.1993.1252. [DOI] [PubMed] [Google Scholar]
  21. Larsen C. P., Ritchie S. C., Hendrix R., Linsley P. S., Hathcock K. S., Hodes R. J., Lowry R. P., Pearson T. C. Regulation of immunostimulatory function and costimulatory molecule (B7-1 and B7-2) expression on murine dendritic cells. J Immunol. 1994 Jun 1;152(11):5208–5219. [PubMed] [Google Scholar]
  22. Lee S. W., Tsou A. P., Chan H., Thomas J., Petrie K., Eugui E. M., Allison A. C. Glucocorticoids selectively inhibit the transcription of the interleukin 1 beta gene and decrease the stability of interleukin 1 beta mRNA. Proc Natl Acad Sci U S A. 1988 Feb;85(4):1204–1208. doi: 10.1073/pnas.85.4.1204. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Lew W., Oppenheim J. J., Matsushima K. Analysis of the suppression of IL-1 alpha and IL-1 beta production in human peripheral blood mononuclear adherent cells by a glucocorticoid hormone. J Immunol. 1988 Mar 15;140(6):1895–1902. [PubMed] [Google Scholar]
  24. Luedke C. E., Cerami A. Interferon-gamma overcomes glucocorticoid suppression of cachectin/tumor necrosis factor biosynthesis by murine macrophages. J Clin Invest. 1990 Oct;86(4):1234–1240. doi: 10.1172/JCI114829. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Moser M., De Smedt T., Sornasse T., Tielemans F., Chentoufi A. A., Muraille E., Van Mechelen M., Urbain J., Leo O. Glucocorticoids down-regulate dendritic cell function in vitro and in vivo. Eur J Immunol. 1995 Oct;25(10):2818–2824. doi: 10.1002/eji.1830251016. [DOI] [PubMed] [Google Scholar]
  26. Munck A., Guyre P. M., Holbrook N. J. Physiological functions of glucocorticoids in stress and their relation to pharmacological actions. Endocr Rev. 1984 Winter;5(1):25–44. doi: 10.1210/edrv-5-1-25. [DOI] [PubMed] [Google Scholar]
  27. Paliogianni F., Ahuja S. S., Balow J. P., Balow J. E., Boumpas D. T. Novel mechanism for inhibition of human T cells by glucocorticoids. Glucocorticoids inhibit signal transduction through IL-2 receptor. J Immunol. 1993 Oct 15;151(8):4081–4089. [PubMed] [Google Scholar]
  28. 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]
  29. Russo-Marie F. Macrophages and the glucocorticoids. J Neuroimmunol. 1992 Oct;40(2-3):281–286. doi: 10.1016/0165-5728(92)90144-a. [DOI] [PubMed] [Google Scholar]
  30. Schuhmachers G., Xu S., Bergstresser P. R., Takashima A. Identity and functional properties of novel skin-derived fibroblast lines (NS series) that support the growth of epidermal-derived dendritic cell lines. J Invest Dermatol. 1995 Aug;105(2):225–230. doi: 10.1111/1523-1747.ep12317512. [DOI] [PubMed] [Google Scholar]
  31. Shadduck R. K., Waheed A., Mangan K. F., Rosenfeld C. S. Preparation of a monoclonal antibody directed against the receptor for murine colony-stimulating factor-1. Exp Hematol. 1993 Apr;21(4):515–520. [PubMed] [Google Scholar]
  32. Simon J. C., Cruz P. D., Jr, Bergstresser P. R., Tigelaar R. E. Low dose ultraviolet B-irradiated Langerhans cells preferentially activate CD4+ cells of the T helper 2 subset. J Immunol. 1990 Oct 1;145(7):2087–2091. [PubMed] [Google Scholar]
  33. 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]
  34. Stam W. B., Van Oosterhout A. J., Nijkamp F. P. Pharmacologic modulation of Th1- and Th2-associated lymphokine production. Life Sci. 1993;53(26):1921–1934. doi: 10.1016/0024-3205(93)90014-t. [DOI] [PubMed] [Google Scholar]
  35. Steinman R. M. The dendritic cell system and its role in immunogenicity. Annu Rev Immunol. 1991;9:271–296. doi: 10.1146/annurev.iy.09.040191.001415. [DOI] [PubMed] [Google Scholar]
  36. Symington F. W., Brady W., Linsley P. S. Expression and function of B7 on human epidermal Langerhans cells. J Immunol. 1993 Feb 15;150(4):1286–1295. [PubMed] [Google Scholar]
  37. Takashima A., Edelbaum D., Kitajima T., Shadduck R. K., Gilmore G. L., Xu S., Taylor R. S., Bergstresser P. R., Ariizumi K. Colony-stimulating factor-1 secreted by fibroblasts promotes the growth of dendritic cell lines (XS series) derived from murine epidermis. J Immunol. 1995 May 15;154(10):5128–5135. [PubMed] [Google Scholar]
  38. Xu S., Ariizumi K., Caceres-Dittmar G., Edelbaum D., Hashimoto K., Bergstresser P. R., Takashima A. Successive generation of antigen-presenting, dendritic cell lines from murine epidermis. J Immunol. 1995 Mar 15;154(6):2697–2705. [PubMed] [Google Scholar]
  39. Xu S., Ariizumi K., Edelbaum D., Bergstresser P. R., Takashima A. Cytokine-dependent regulation of growth and maturation in murine epidermal dendritic cell lines. Eur J Immunol. 1995 Apr;25(4):1018–1024. doi: 10.1002/eji.1830250424. [DOI] [PubMed] [Google Scholar]

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

RESOURCES