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. 1997 Apr 1;99(7):1721–1728. doi: 10.1172/JCI119336

Glucocorticoids decrease tissue mast cell number by reducing the production of the c-kit ligand, stem cell factor, by resident cells: in vitro and in vivo evidence in murine systems.

S Finotto 1, Y A Mekori 1, D D Metcalfe 1
PMCID: PMC507993  PMID: 9120017

Abstract

The local delivery of glucocorticoids to tissues significantly decreases mast cell number. This pharmacologic effect of glucocorticoids is believed to be one of the mechanisms by which glucocorticoids regulate allergic inflammation. To determine the mechanism by which glucocorticoids are able to exert this effect, we first applied the glucocorticoid fluocinonide to mouse dermis and observed that the decrease in mast cell number was associated with an increase in mast cell apoptosis. This did not appear to be due to a direct effect of the glucocorticoid on mast cells, as the addition of 0.01-1.0 microM of the glucocorticoid dexamethasone into stem cell factor (SCF)-dependent mast cell cultures did not enhance mast cell death. However, addition of dexamethasone to cultured fibroblasts did result in a downregulation of SCF mRNA and a significant decrease in SCF protein production. Similarly, immunohistochemistry performed on fluocinonide-treated mouse dermis revealed a decrease in immunoreactive SCF. Administration of SCF at sites of fluocinonide administration to the dermis abolished the mast cell-depleting effect of this glucocorticoid. Thus, glucocorticoids decrease tissue mast cell number by downregulating tissue SCF production required for the survival of local mast cells. This observation may be applicable to the design of improved strategies to treat mast cell-mediated disorders.

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Selected References

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  1. Anderson D. M., Lyman S. D., Baird A., Wignall J. M., Eisenman J., Rauch C., March C. J., Boswell H. S., Gimpel S. D., Cosman D. Molecular cloning of mast cell growth factor, a hematopoietin that is active in both membrane bound and soluble forms. Cell. 1990 Oct 5;63(1):235–243. doi: 10.1016/0092-8674(90)90304-w. [DOI] [PubMed] [Google Scholar]
  2. Auphan N., DiDonato J. A., Rosette C., Helmberg A., Karin M. Immunosuppression by glucocorticoids: inhibition of NF-kappa B activity through induction of I kappa B synthesis. Science. 1995 Oct 13;270(5234):286–290. doi: 10.1126/science.270.5234.286. [DOI] [PubMed] [Google Scholar]
  3. Aye M. T., Hashemi S., Leclair B., Zeibdawi A., Trudel E., Halpenny M., Fuller V., Cheng G. Expression of stem cell factor and c-kit mRNA in cultured endothelial cells, monocytes and cloned human bone marrow stromal cells (CFU-RF). Exp Hematol. 1992 May;20(4):523–527. [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. 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]
  6. Daëron M., Malbec O., Latour S., Arock M., Fridman W. H. Regulation of high-affinity IgE receptor-mediated mast cell activation by murine low-affinity IgG receptors. J Clin Invest. 1995 Feb;95(2):577–585. doi: 10.1172/JCI117701. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Flanagan J. G., Chan D. C., Leder P. Transmembrane form of the kit ligand growth factor is determined by alternative splicing and is missing in the Sld mutant. Cell. 1991 Mar 8;64(5):1025–1035. doi: 10.1016/0092-8674(91)90326-t. [DOI] [PubMed] [Google Scholar]
  8. Flanagan J. G., Leder P. The kit ligand: a cell surface molecule altered in steel mutant fibroblasts. Cell. 1990 Oct 5;63(1):185–194. doi: 10.1016/0092-8674(90)90299-t. [DOI] [PubMed] [Google Scholar]
  9. Galli S. J., Arizono N., Murakami T., Dvorak A. M., Fox J. G. Development of large numbers of mast cells at sites of idiopathic chronic dermatitis in genetically mast cell-deficient WBB6F1-W/Wv mice. Blood. 1987 Jun;69(6):1661–1666. [PubMed] [Google Scholar]
  10. Galli S. J., Iemura A., Garlick D. S., Gamba-Vitalo C., Zsebo K. M., Andrews R. G. Reversible expansion of primate mast cell populations in vivo by stem cell factor. J Clin Invest. 1993 Jan;91(1):148–152. doi: 10.1172/JCI116164. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Godin I., Deed R., Cooke J., Zsebo K., Dexter M., Wylie C. C. Effects of the steel gene product on mouse primordial germ cells in culture. Nature. 1991 Aug 29;352(6338):807–809. doi: 10.1038/352807a0. [DOI] [PubMed] [Google Scholar]
  12. Goldsmith P., McGarity B., Walls A. F., Church M. K., Millward-Sadler G. H., Robertson D. A. Corticosteroid treatment reduces mast cell numbers in inflammatory bowel disease. Dig Dis Sci. 1990 Nov;35(11):1409–1413. doi: 10.1007/BF01536749. [DOI] [PubMed] [Google Scholar]
  13. Gordon J. R., Galli S. J. Release of both preformed and newly synthesized tumor necrosis factor alpha (TNF-alpha)/cachectin by mouse mast cells stimulated via the Fc epsilon RI. A mechanism for the sustained action of mast cell-derived TNF-alpha during IgE-dependent biological responses. J Exp Med. 1991 Jul 1;174(1):103–107. doi: 10.1084/jem.174.1.103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Haak-Frendscho M., Ridgway J., Shields R., Robbins K., Gorman C., Jardieu P. Human IgE receptor alpha-chain IgG chimera blocks passive cutaneous anaphylaxis reaction in vivo. J Immunol. 1993 Jul 1;151(1):351–358. [PubMed] [Google Scholar]
  15. Heinrich M. C., Dooley D. C., Freed A. C., Band L., Hoatlin M. E., Keeble W. W., Peters S. T., Silvey K. V., Ey F. S., Kabat D. Constitutive expression of steel factor gene by human stromal cells. Blood. 1993 Aug 1;82(3):771–783. [PubMed] [Google Scholar]
  16. Iemura A., Tsai M., Ando A., Wershil B. K., Galli S. J. The c-kit ligand, stem cell factor, promotes mast cell survival by suppressing apoptosis. Am J Pathol. 1994 Feb;144(2):321–328. [PMC free article] [PubMed] [Google Scholar]
  17. Johnson A. R., Hugli T. E., Müller-Eberhard H. J. Release of histamine from rat mast cells by the complement peptides C3a and C5a. Immunology. 1975 Jun;28(6):1067–1080. [PMC free article] [PubMed] [Google Scholar]
  18. King S. J., Miller H. R., Newlands G. F., Woodbury R. G. Depletion of mucosal mast cell protease by corticosteroids: effect on intestinal anaphylaxis in the rat. Proc Natl Acad Sci U S A. 1985 Feb;82(4):1214–1218. doi: 10.1073/pnas.82.4.1214. [DOI] [PMC free article] [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. Lavker R. M., Schechter N. M. Cutaneous mast cell depletion results from topical corticosteroid usage. J Immunol. 1985 Oct;135(4):2368–2373. [PubMed] [Google Scholar]
  21. Longley B. J., Jr, Morganroth G. S., Tyrrell L., Ding T. G., Anderson D. M., Williams D. E., Halaban R. Altered metabolism of mast-cell growth factor (c-kit ligand) in cutaneous mastocytosis. N Engl J Med. 1993 May 6;328(18):1302–1307. doi: 10.1056/NEJM199305063281803. [DOI] [PubMed] [Google Scholar]
  22. Malone D. G., Wilder R. L., Saavedra-Delgado A. M., Metcalfe D. D. Mast cell numbers in rheumatoid synovial tissues. Correlations with quantitative measures of lymphocytic infiltration and modulation by antiinflammatory therapy. Arthritis Rheum. 1987 Feb;30(2):130–137. doi: 10.1002/art.1780300202. [DOI] [PubMed] [Google Scholar]
  23. Martin F. H., Suggs S. V., Langley K. E., Lu H. S., Ting J., Okino K. H., Morris C. F., McNiece I. K., Jacobsen F. W., Mendiaz E. A. Primary structure and functional expression of rat and human stem cell factor DNAs. Cell. 1990 Oct 5;63(1):203–211. doi: 10.1016/0092-8674(90)90301-t. [DOI] [PubMed] [Google Scholar]
  24. Mekori Y. A., Oh C. K., Metcalfe D. D. IL-3-dependent murine mast cells undergo apoptosis on removal of IL-3. Prevention of apoptosis by c-kit ligand. J Immunol. 1993 Oct 1;151(7):3775–3784. [PubMed] [Google Scholar]
  25. Mican J. A., Arora N., Burd P. R., Metcalfe D. D. Passive cutaneous anaphylaxis in mouse skin is associated with local accumulation of interleukin-6 mRNA and immunoreactive interleukin-6 protein. J Allergy Clin Immunol. 1992 Nov;90(5):815–824. doi: 10.1016/0091-6749(92)90107-d. [DOI] [PubMed] [Google Scholar]
  26. Pipkorn U., Hammarlund A., Enerbäck L. Prolonged treatment with topical glucocorticoids results in an inhibition of the allergen-induced weal-and-flare response and a reduction in skin mast cell numbers and histamine content. Clin Exp Allergy. 1989 Jan;19(1):19–25. doi: 10.1111/j.1365-2222.1989.tb02338.x. [DOI] [PubMed] [Google Scholar]
  27. Plaut M., Pierce J. H., Watson C. J., Hanley-Hyde J., Nordan R. P., Paul W. E. Mast cell lines produce lymphokines in response to cross-linkage of Fc epsilon RI or to calcium ionophores. Nature. 1989 May 4;339(6219):64–67. doi: 10.1038/339064a0. [DOI] [PubMed] [Google Scholar]
  28. Ramos B. F., Zhang Y., Jakschik B. A. Neutrophil elicitation in the reverse passive Arthus reaction. Complement-dependent and -independent mast cell involvement. J Immunol. 1994 Feb 1;152(3):1380–1384. [PubMed] [Google Scholar]
  29. SALVATO G. Mast cells in bronchial connective tissue of man; importance of such cells in allergic tissue injury. Experientia. 1959 Aug 15;15:308–309. doi: 10.1007/BF02158539. [DOI] [PubMed] [Google Scholar]
  30. Scheinman R. I., Cogswell P. C., Lofquist A. K., Baldwin A. S., Jr Role of transcriptional activation of I kappa B alpha in mediation of immunosuppression by glucocorticoids. Science. 1995 Oct 13;270(5234):283–286. doi: 10.1126/science.270.5234.283. [DOI] [PubMed] [Google Scholar]
  31. Tsai M., Shih L. S., Newlands G. F., Takeishi T., Langley K. E., Zsebo K. M., Miller H. R., Geissler E. N., Galli S. J. The rat c-kit ligand, stem cell factor, induces the development of connective tissue-type and mucosal mast cells in vivo. Analysis by anatomical distribution, histochemistry, and protease phenotype. J Exp Med. 1991 Jul 1;174(1):125–131. doi: 10.1084/jem.174.1.125. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Yee N. S., Paek I., Besmer P. Role of kit-ligand in proliferation and suppression of apoptosis in mast cells: basis for radiosensitivity of white spotting and steel mutant mice. J Exp Med. 1994 Jun 1;179(6):1777–1787. doi: 10.1084/jem.179.6.1777. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Zsebo K. M., Williams D. A., Geissler E. N., Broudy V. C., Martin F. H., Atkins H. L., Hsu R. Y., Birkett N. C., Okino K. H., Murdock D. C. Stem cell factor is encoded at the Sl locus of the mouse and is the ligand for the c-kit tyrosine kinase receptor. Cell. 1990 Oct 5;63(1):213–224. doi: 10.1016/0092-8674(90)90302-u. [DOI] [PubMed] [Google Scholar]
  34. Zsebo K. M., Wypych J., McNiece I. K., Lu H. S., Smith K. A., Karkare S. B., Sachdev R. K., Yuschenkoff V. N., Birkett N. C., Williams L. R. Identification, purification, and biological characterization of hematopoietic stem cell factor from buffalo rat liver--conditioned medium. Cell. 1990 Oct 5;63(1):195–201. doi: 10.1016/0092-8674(90)90300-4. [DOI] [PubMed] [Google Scholar]

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