European Journal of Clinical Pharmacology

, Volume 45, Supplement 1, pp S17–S20 | Cite as

Anti-inflammatory effects of glucocorticoids and cyclosporin A on human basophils

  • G. Marone
  • C. Stellato
  • A. Renda
  • A. Genovese
Article

Summary

Pro-inflammatory and vasoactive mediators released from human basophils and mast cells play a role in several inflammatory and immune disorders. It was recently demonstrated that cyclosporin A (CsA) exerts anti-inflammatory effects by inhibiting the release of preformed and de novo synthesized mediators from human basophils [1]. This study compared the effects of pharmacological concentrations of deflazacort (DFZ) and prednisolone (PRED) on the anti-IgE-mediated release of preformed (histamine) and de novo synthesized (leukotriene C4: [LTC4]) mediators from basophils. Basophils were cultured for 18 hours in the presence of pharmacological concentrations of DFZ (10−8 to 3 × 10−6 M). DFZ inhibited the anti-IgE-mediated release of histamine and LTC4 from basophils in a concentration-dependent manner (6–40 %), and had a similar efficacy and potency to PRED. The effect of DFZ (10−8 to 10−8 M) in combination with CsA on the immunological release of histamine and LTC4 from basophils was also evaluated. An 18-hour incubation of basophils with DFZ (10−8 M) followed by a short (15-minute) incubation with CsA (30 ng/ml) resulted in an additive inhibition of the release of histamine and LTC4. The additive anti-inflammatory effect of these drugs makes them interesting candidates for future controlled clinical trials in inflammatory diseases in which basophil-derived mediators play a relevant role.

Key words

Basophils Cyclosporin A Corticosteroids deflazacort histamine leukotriene C4 
This is a preview of subscription content, log in to check access.

References

  1. 1.
    Cirillo R, Triggiani MSiri LCiccarelli APettit GR, Condorelli M, Marone G (1990) Cyclosporin A rapidly inhibits mediator release from human basophils presumably by interacting with cyclophilin. J Immunol 144: 3891–3897Google Scholar
  2. 2.
    Siegel SC (1985) Overview of corticosteroid therapy. J Allergy Clin Immunol 76: 312–320Google Scholar
  3. 3.
    Schleimer RP (1990) Effects of glucocorticoids on inflammatory cells relevant to their therapeutic applications in asthma. Am Rev Respir Dis 141: S59–69Google Scholar
  4. 4.
    Schleimer RP (1988) Glucocorticosteroids. Their mechanism of action and use in allergic diseases. In: Middleton E Jr, Reed CE, Ellis EF, Adkinson NF Jr, Yunginger JW (eds) Allergy. Principles and practice. l. Mosby, St. Louis, pp 739–765Google Scholar
  5. 5.
    Gray RES, Doherty SM, Galloway J, Coulton L, de Broe M, Kanis JA (1991) A double-blind study of deflazacort and prednisolone in patients with chronic inflammatory disorders. Arth Rheum 34: 287–295Google Scholar
  6. 6.
    Kahan BD (1989) Cyclosporine. N Engl J Med 321: 1725–1738Google Scholar
  7. 7.
    Nussenblatt RB, Rook AH, Wacker WB, Palestine AG, Scher I, Gery I (1983) Treatment of intraocular inflammatory diseases with cyclosporin A. Lancet II: 235–238Google Scholar
  8. 8.
    Weinblatt ME, Coblyn JS, Fraser PA, Anderson RJ, Spragg J, Trentham DE, Austen KF (1987) Cyclosporin A treatment of refractory rheumatoid arthritis. Arth Rheum 30: 11–17Google Scholar
  9. 9.
    Bougneres PF, Carel JC, Boitard C et al. (1988) Factors associated with early remission of type I diabetes in children treated with cyclosporine. N Engl J Med 318: 663–670Google Scholar
  10. 10.
    Brynskow J, Freund L, Rasmussen, et al. (1989) A placebocontrolled, double-blind, randomized trial of cyclosporine therapy in active chronic Crohn's disease. N Engl J Med 321: 845–850Google Scholar
  11. 11.
    Alexander AG, Barnes NC, Kay AB (1992) Cyclosporin A (CyA) in corticosteroid-dependent chronic severe asthma. A randomised double-blind placebo-controlled crossover trial. Lancet 339: 324–328Google Scholar
  12. 12.
    Munro CS, Higgins EM, Marks JM, Daly BM, Friedmann PS, Shuster S (1991) Cyclosporin A in atopic dermatitis: therapeutic response is dissociated from effects on allergic reactions. Br J Dermatol 124: 43–48Google Scholar
  13. 13.
    Secchi AG, Tognon MS, Leonardi A (1990) Topical use of cyclosporine in the treatment of vernal keratoconjunctivitis. Am J Ophthalmol 110: 641–645Google Scholar
  14. 14.
    Marone G, de Paulis A, Ciecarelli A, Casolaro V, Cirillo R (1991) Mechanism(s) of action of cyclosporin A. Seminars Clin Immunol 2: 11–16Google Scholar
  15. 15.
    Marone G (1992) Immunosuppressive treatment of chronic asthma. In: Lichtenstein LM, Fauci AS (eds) Current therapy in allergy, immunology, and rheumatology. 4. Mosby, Philadelphia, pp 368–371Google Scholar
  16. 16.
    Casolaro V, Galeone D, Giacummo A, Sanduzzi A, Melillo G, Marone G (1989) Human basophil/mast cell releasability. V Functional comparisons of cells obtained from peripheral blood, lung parenchyma and from bronchoalveolar lavage in asthmatics. Am Rev Respir Dis 139: 1375–1382Google Scholar
  17. 17.
    Marone G, Giugliano R, Lembo G, Ayala F (1986) Human basophil releasability. II. Changes in basophil releasability in patients with atopic dermatitis. J Invest Dermatol 87: 19–23Google Scholar
  18. 18.
    Dvorak AM, Monahan RA, Osage JE, Dickersin GR (1980) Crohn's disease transmission electron microscopic studies. II. Immunologic inflammatory response. Alterations of mast cells, basophils, eosinophils, and the microvasculature. Human Pathol 11: 606–619Google Scholar
  19. 19.
    de Paulis A, Valentini G, Spadaro G, Lupoli S, Tirri G, Marone G (1991) Human basophil releasability. VIII. Increased basophil releasability in patients with scleroderma. Arth Rheum 34: 1289–1296Google Scholar
  20. 20.
    Colvin RB, Dvorak HE (1974) Basophils and mast cells in renal allograft rejection. Lancet I: 212–214Google Scholar
  21. 21.
    Schleimer RP, Lichtenstein LM, Gillespie E (1981) Inhibition of basophil histamine release by anti-inflammatory steroids. Nature 292: 454–455Google Scholar
  22. 22.
    Schleimer RP, Davidson DA, Peters SP, Lichtenstein LM (1985) Inhibition of basophil leukotriene release by anti-inflammatory steroids. Int Arch Allergy Appl Immunol 77: 241–243Google Scholar
  23. 23.
    Krbnke M, Leonard WJ, Depper JM, Arya SK, Wong-Staal F, Gallo RC, Waldmann TA, Greene WC (1984) Cyclosporin A inhibits T -cell growth factor gene expression at the level of mRNA transcription. Proc Natl Acad Sci USA 81: 5214–5218Google Scholar
  24. 24.
    Marone G, Cirillo R, Ciccarelli A, de Paulis A, Condorelli M (1990) Mechanism of action of cyclosporin A in human inflammatory cells. In: Bonomo L (ed) Cyclosporin in autoimmune diseases. Il Pensiero Scientifico, Rome, pp 1–10Google Scholar
  25. 25.
    Casolaro V, Spadaro G, Patella V, Marone G (1993) In vivo characterization of the anti-inflammatory effect of cyclosporin A. J Clin Invest (submitted for publication)Google Scholar
  26. 26.
    Casolaro V, Spadaro G, Marone G (1990) Human basophil releasability. VI. Changes in basophil releasability in patients with allergic rhinitis or bronchial asthma. Am Rev Respir Dis 142: 1108–1111Google Scholar
  27. 27.
    Marone G, Columbo M, Triggiani M, Cirillo R, Genovese A, Formisano S (1987) Inhibition of IgE-mediated histamine and peptide leukotriene release from human basophils and mast cells by forskolin. Biochem Pharmacol 36: 13–20Google Scholar
  28. 28.
    Hayes EC, Lombardo DL, Girard JY, Maycock AL, Rokach J, Rosenthal AS, Young RN, Egan RW, Zweerink HJ (1983) Measuring leukotrienes of slow reacting substance of anaphylaxis: development of a specific radioimmunoassay. J Immunol 131: 429–432Google Scholar
  29. 29.
    Schefler WC (1988) Statistics for Health Professionals. Addison-Wesley, Reading, MAGoogle Scholar
  30. 0.
    de Paulis A, Cirillo R, Ciccarelli A, Condorelli M, Marone G (1991) FK-506, a potent novel inhibitor of the release of proinflammatory mediators from human FcεRI+ cells. J Immunol 146: 2374–2381Google Scholar
  31. 31.
    Genovese A, Spadaro G, Ciccarelli A, de Paulis A, Cirillo R, Marone G (1992) Modulation of mediator release from human FcεRI+ cells. In: Olivieri D, Barnes P, Hurd S, Folco G (eds) Asthma treatment. A multidisciplinary approach. Plenum, New York, pp 131–144Google Scholar
  32. 32.
    Marone G (1993) In vitro and in vivo modulation of human mast cells and basophils. In: Holgate ST, Austen KF, Lichtenstein LM, Kay AB (eds) Asthma: physiology and treatment: fourth international symposium. Academic Press, New York, pp 419–433Google Scholar
  33. 33.
    Casolaro V, Stellato C, de Crescenzo G, Triggiani M, Marone G: Human mast cells, basophils and their mediators. In: Olivieri D, Barnes P, Hurd S, Folco G (eds) Asthma treatment. A multidisciplinary approach. Plenum, New York, pp 63—79Google Scholar
  34. 34.
    Larsson EL (1980) Cyclosporin A and dexamethasone suppress T cell responses by selectively acting at distinct sites of the triggering process. J Immunol 124: 2828–2833 35. Gordon D, Nouri AME (1981) Comparison of the inhibition by glucocorticosteroids and cyclosporin A of mitogen-stimulated human lymphocyte proliferation. Clin Exp Immunol 44: 287-294 36. Reed JC, Abidi AH, Alpers JD, Hoover RG, Robb RJ, Nowell PC (1986) Effect of cyclosporin A and dexamethasone on interleukin 2 receptor gene expression. J Immunol 137: 150-154 37. Chiara MD, Sobrino F (1991) Modulation of the inhibition of respiratory burst in mouse macrophages by cyclosporin A: effect of in vivo treatment, glucocorticoids and the state of activation of cells. Immunology 72:133-137Google Scholar
  35. 38.
    Starzl TE, Klintmalm GB, Porter KA, Iwatsuki S, Schröter GPJ (1981) Liver transplantation with use of cyclosporin A and prednisone. N Engl J Med 305: 266–269Google Scholar

Copyright information

© Springer-Verlag 1993

Authors and Affiliations

  • G. Marone
    • 1
  • C. Stellato
    • 1
  • A. Renda
    • 2
  • A. Genovese
    • 1
  1. 1.Division of Clinical Immunology and AllergyUniversity of Naples Federico II, School of MedicineNaplesItaly
  2. 2.Division of General Surgery and Organ TransplantationUniversity of Naples Federico II, School of MedicineNaplesItaly

Personalised recommendations