Inflammation pp 95-107 | Cite as

Suppression of Mast Cell Activation by Glucocorticoid

  • Hideshi Yoshikawa
  • Kachio Tasaka


Mast cells play a critical role in allergic diseases. When mast cells are activated by cross-linking of their high affinity IgE receptors by the antigen and IgE antibodies, release of chemical mediators is followed by secretion of multiple cytokines. We report that IL-3-dependent mucosal-type mast cells undergo apoptosis when IL-3 is withdrawn. In addition, cross-linking of high affinity IgE receptors prevents apoptosis of mast cells by paracrine mechanisms, producing IL-3, IL-4 and granulocyte/macrophage colony-stimulating factor (GM-CSF). However, the secretion of endogenous growth factors are not enough for cell survival, whereas IL-4 induces cell aggregation by expressing adhesion molecules such as leukocyte function-associated antigen 1 (LFA-1), and makes it reactive to endogenous growth factors by contact cell to cell interaction. On the other hand, dexamethazone down-regulates the expression of intracelluar adhesion molecule 1 (ICAM-1) and IL-4 in activated mast cells, by which the self-aggregation of mast cells is inhibited and apoptosis is induced. Thus, glucocorticoids suppress mast cell survival by inhibiting IL-4 production and expression of adhesion molecules.

Key words

allergy mast cell glucocorticoid cytokine adhesion molecule. 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Ben-Sasson S. Z., LeGros G., Conrad D. H., Finkelman F. D. and Paul W. E. (1990): Cross-linking Fc receptors stimulates splenic non-B, non-T cells to secrete interleukin 4 and other lymphokines. Proc. Natl. Acad. Sci. USA, 87, 1421–1425.PubMedCrossRefGoogle Scholar
  2. Boumpas D. T., Anastassiou E. D., Older S. A., Tsokos G. C., Nelson D. L. and Bolow J. E. (1991): Dexamethazone inhibits human interleukin 2 but not interleukin 2 receptor gene expression in vitro at the level of nuclear transcription. J. Clin. Invest., 87, 1739–1747.PubMedCrossRefGoogle Scholar
  3. Bradding P., Feather I. H., Howarth P. H., Mueller R., Roberts J. A., Britten K., Bews J. P. A., Hunt T. C., Okayama Y., Heusser C. H., Bullock G. R., Church M. K. and Holgate S. T. (1992): Interleukin 4 is localized to and released by human mast cells. J. Exp. Med., 176, 1381–1386.PubMedCrossRefGoogle Scholar
  4. Corrigan C. T. and Kay A. B. (1992): T cells and eosinophils in the pathogenesis of asthma. Immunol. Today, 13, 501–507.PubMedCrossRefGoogle Scholar
  5. Cronstein B. N., Kimmel S. C., Levin R. I., Martiniuk E and Weissmann G. (1992): A mechanism for the anti-inflammatory effects of corticosteroids: the glucocorticoid receptor regulates leukocyte adhesion to endothelial cells and expression of endothelial-leukocyte adhesion molecule 1 and intercellular adhesion molecule 1. Proc. Natl. Acad. Sci. USA, 89, 9991–9995.PubMedCrossRefGoogle Scholar
  6. Finotto S., Mekori Y. A. and Metcalfe D. D. (1997): Glucocorticoids decrease tissue mast cell number by reducing the production of the c-kit ligand, stem cell factor, by resident cells. J. Clin. Invest., 99, 1721–1728.PubMedCrossRefGoogle Scholar
  7. Henkel G. and Brown M. A. (1994): PU. 1 and GATA: components of a mast cell-specific interleukin 4 intronic enhancer. Proc. Natl. Acad. Sci. USA, 91, 7737–7741.PubMedCrossRefGoogle Scholar
  8. Kamei Y., Xu L., Heinzel T., Torchia J., Kurosawa R., Gloss B., Lin S. C., Heyman R. A., Rose D. W., Glass C. K. and Rosenfeld M. G. (1996): A CBP integrator complex mediates transcriptional activation and AP-1 inhibition by nuclear receptors. Cell, 85, 403–414.PubMedCrossRefGoogle Scholar
  9. Kim J. I., Ho I. C., Grusby M. J. and Glimcher L. H. (1999): The transcription factor c-Maf controls the production of interleukin-4 but not other Th2 cytokines. Immunity, 10, 745–751.PubMedCrossRefGoogle Scholar
  10. Kraneveld A. D., Ark I. V., Linde H. J. V. D., Fattah D., Nijkamp R. P. and Oosterhout A. J. M. V. (1997): Antibody to very late activation antigen 4 prevents interleukin-5-induced airway hyperresponsiveness and eosinophil infiltration in the airways of guinea pigs. J. Allergy Clin. Immunol., 100, 242–250.PubMedCrossRefGoogle Scholar
  11. Kuhn R., Rajewsky K. and Muller W. (1991): Generation and analysis of interleukin-4 deficient mice. Science, 254, 707–710.PubMedCrossRefGoogle Scholar
  12. Makino Y., Yoshikawa N., Okamoto K., Hirota K., Yodoi J., Makino I. and Tanaka H. (1999): Direct association with thioredoxin allows redox regulation of glucocorticoid receptor function. J. Biol. Chem., 274, 3182–3188.PubMedCrossRefGoogle Scholar
  13. Matsuda H., Watanabe N., Geba G. P., Sperl J., Tsudzuki M., Hiroi J., Matsumoto M., Ushio H., Saito S., Askenase P. W. and Ra C. (1997): Development of atopic dermatitis-like skin lesion with IgE hyperproduction in NC/Nga mice. Int. Immunol., 9, 461–466.PubMedCrossRefGoogle Scholar
  14. Nieto M. A., Gonzalez A., Gambon R, Diaz-Espada E. and Lopez-Rivas A. (1992): Apoptosis in human thymocytes after treatment with glucocorticoids. Clin. Exp. Immunol., 88, 341–344.PubMedCrossRefGoogle Scholar
  15. Okamoto K., Tanaka H., Ogawa H., Makino Y., Eguchi H., Hayashi S., Yoshikawa N., Poellinger L., Umesono K. and Makino I. (1999): Redox-dependent regulation of nuclear import of the glucocorticoid receotor. J. Biol. Chem., 274, 10363–10371.PubMedCrossRefGoogle Scholar
  16. Paliogianni F., Raptis A., Ahuja S. S., Najjar S. M. and Boumpas D. T. (1993): Negative transcriptional regulation of human interleukin 2 (IL-2) gene by glucocorticoids through interference with nuclear transcription factors AP-1 and NF-AT. J. Clin. Invest., 91, 1481–1489.PubMedCrossRefGoogle Scholar
  17. Piccinni M. P., Macchia D., Parronchi P., Giudizi M. G., Bani D., Alterini R., Grossi A., Ricci M., Maggi E. and Romagnani S. (1991): Human bone-marrow non B, non T-cells produce interleukin 4 in response to cross-linkage of Fcc and Fcy receptors. Proc. Natl. Acad. Sci. USA, 88, 8656–8660.PubMedCrossRefGoogle Scholar
  18. Romagnani S. (1992): Induction of Thl and Th2 responses: a key role for the “natural” immune response? Immunol. Today, 13, 379–381.Google Scholar
  19. Rooney J. W., Hoey T. and Glimcher L. H. (1995): Coordinate and cooperative roles for NF-AT and AP-1 in the regulation of the murine IL-4 gene. Immunity, 2, 473–483.PubMedCrossRefGoogle Scholar
  20. Secrist H., Chelen C. J., Wen Y., Marshall J. D. and Umetsu D. T. (1993): Allergen immunotherapy decreases interleukin 4 production in CD4’ T cells from allergic individuals. J. Exp. Med., 178, 2123–2130.PubMedCrossRefGoogle Scholar
  21. Shapira S. K., Jabara H. H., Thienes C. P., Ahern D. J., Vercelli D., Gould H. J. and Geha R. S. (1991): Deletional switch recombination occurs in interleukin-4 induced isotype switching to IgE expression by human B cells. Proc. Natl. Acad. Sci. USA, 88, 7528–7532.PubMedCrossRefGoogle Scholar
  22. Sherman M. A., Nachman T. Y. and Brown M. A. (1999): Cutting edge: IL-4 production by mast cells does not require c-maf. J. Immunol., 163, 1733–1736.PubMedGoogle Scholar
  23. Smith T. J., Ducharme L. A. and Weis J. H. (1994): Preferential expression of interleukin-12 or interleukin-4 by murine bone marrow mast cells derived in mast cell growth factor or interleukin-3. Eur. J. Immunol., 24, 822–826.PubMedCrossRefGoogle Scholar
  24. Tepper R. I., Levinson D. A., Stanger B. Z., Campos-Torres J., Abbas A. K. and Leder P. (1990): IL-4 induces allergic-like inflammatory disease and alters T cell development in trans-genic mice. Cell, 62, 457–467.PubMedCrossRefGoogle Scholar
  25. Thompson-Snipes L. A., Dhar V., Bond M. W., Mosmann T. R., Moore K. W. and Rennick D. M. (1991): Interleukin 10: a novel stimulatory factor for mast cells and their progenitors. J. Exp. Med.. 173, 507–510.PubMedCrossRefGoogle Scholar
  26. Vajdy M., Kosco-Vilbois M. H., Kopf M., Kohler G. and Lycke N. (1995): Impaired mucosal immune responses in interleukin 4-targeted mice. J. Exp. Med., 181, 41–53.PubMedCrossRefGoogle Scholar
  27. Valent P., Spanblochel E., Sperr W. R., Sillaber C., Zsebo K. M., Agis H., Strobl H., Geissler K., Bettelheim P. and Lechner K. (1992): Induction of differentiation of human mast cells from bone marrow and peripheral blood mononuclear cells by recombinant human stem cell factor/kit-ligand in long-term culture. Blood, 80, 2237–2245.PubMedGoogle Scholar
  28. Walsh L. J., Trinchieri G., Waldorf H. A., Whitaker D. and Mupphy G. F. (1991): Human dermal mast cells contain and release tumor necrosis factor a, which induces endothelial leukocyte adhesion molecule 1. Proc. Natl. Acad. Sci. USA, 88, 4220–4224.PubMedCrossRefGoogle Scholar
  29. Wissink S., van Heerde E. C., van der Burg B. and van der Saag P. T. (1998): A dual mechanism mediates repression of NF-KB activity by glucocorticoids. Mol. Endocrinol., 12, 355–363.PubMedCrossRefGoogle Scholar
  30. Wu C. Y., Fargeas C., Nakajima T. and Delespesse G. (1991): Glucocorticoids suppress the production of interleukin 4 by human lymphocytes. Eur. J. Immunol., 21, 2645–2647.PubMedCrossRefGoogle Scholar
  31. Ying S., Durham S. R., Jacobson M. R., Rak S., Masuyama K., Lowhagem O., Kay A. B. and Hamid Q. A. (1994): T lymphocytes and mast cells express messenger RNA for interleukin-4 in the nasal mucosa in allergen-induced rhinitis. Immunology, 82, 200–206.PubMedGoogle Scholar
  32. Yoshikawa H., Nakajima Y. and Tasaka K. (1999): Glucocorticoid suppresses autocrine survival of mast cells by inhibiting IL-4 production and ICAM-1 expression. J. Immunol., 162, 6162–6170.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2001

Authors and Affiliations

  • Hideshi Yoshikawa
    • 1
  • Kachio Tasaka
    • 1
  1. 1.Department of Parasitology and ImmunologyYamanashi Medical UniversityTamaho-cho, YamanashiJapan

Personalised recommendations