Skip to main content
NCBI home page
Infection and Immunity logoLink to Infection and Immunity
. 1993 Nov;61(11):4870–4877. doi: 10.1128/iai.61.11.4870-4877.1993

Prevention of corticosteroid-induced suppression of human polymorphonuclear leukocyte-induced damage of Aspergillus fumigatus hyphae by granulocyte colony-stimulating factor and gamma interferon.

E Roilides 1, K Uhlig 1, D Venzon 1, P A Pizzo 1, T J Walsh 1
PMCID: PMC281246  PMID: 7691757

Abstract

Neutrophils (PMNs) are a critical line of defense against Aspergillus fumigatus infection. Increased frequency of invasive aspergillosis has been observed in patients receiving corticosteroids, suggesting a deleterious effect of these compounds on PMN antifungal function. To investigate this hypothesis and to determine the potential preventive utility of granulocyte colony-stimulating factor (G-CSF) and gamma interferon (IFN-gamma), the effects of hydrocortisone (HCS) and dexamethasone (DXS) on PMN-induced damage of Aspergillus fumigatus hyphae were studied with or without pretreatment of PMNs with G-CSF and IFN-gamma. PMNs treated with HCS (> or = 3,000 microM) or DXS (> or = 10 microM) during a 2-h colorimetric tetrazolium metabolic assay (using methylthiotetrazolium) showed suppressed percentage of hyphal damage (P < 0.02). In addition, both HCS (> or = 30 microM) and DXS (> or = 1 microM) significantly suppressed oxidative burst measured as superoxide anion release by PMNs in response to opsonized and nonopsonized hyphae as well as to N-formylmethionyl leucyl phenylalanine. Pretreatment of PMNs with G-CSF (4,000 U/ml) and/or IFN-gamma (100 and 1,000 U/ml) for 90 min prevented the suppression of hyphal damage that occurred in the presence of HCS (3,000 microM; P < 0.01) or DXS (10 microM; P < or = 0.001). G-CSF (4,000 U/ml) and IFN-gamma (100 U/ml) combined had an additive effect on increasing the antifungal activity of HCS-treated but not of DXS-treated PMNs compared with IFN-gamma alone (P = 0.015). Thus, these findings reveal that corticosteroids impair PMN function in response to A. fumigatus and that G-CSF and IFN-gamma prevent this impairment.

Full text

PDF
4870

Selected References

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

  1. Amezaga M. A., Bazzoni F., Sorio C., Rossi F., Cassatella M. A. Evidence for the involvement of distinct signal transduction pathways in the regulation of constitutive and interferon gamma-dependent gene expression of NADPH oxidase components (gp91-phox, p47-phox, and p22-phox) and high-affinity receptor for IgG (Fc gamma R-I) in human polymorphonuclear leukocytes. Blood. 1992 Feb 1;79(3):735–744. [PubMed] [Google Scholar]
  2. Blowers L. E., Jayson M. I., Jasani M. K. Effect of dexamethasone on polypeptides synthesised in polymorphonuclear leucocytes. FEBS Lett. 1985 Feb 25;181(2):362–366. doi: 10.1016/0014-5793(85)80293-3. [DOI] [PubMed] [Google Scholar]
  3. Bonilla M. A., Gillio A. P., Ruggeiro M., Kernan N. A., Brochstein J. A., Abboud M., Fumagalli L., Vincent M., Gabrilove J. L., Welte K. Effects of recombinant human granulocyte colony-stimulating factor on neutropenia in patients with congenital agranulocytosis. N Engl J Med. 1989 Jun 15;320(24):1574–1580. doi: 10.1056/NEJM198906153202402. [DOI] [PubMed] [Google Scholar]
  4. Buyon J. P., Korchak H. M., Rutherford L. E., Ganguly M., Weissmann G. Female hormones reduce neutrophil responsiveness in vitro. Arthritis Rheum. 1984 Jun;27(6):623–630. doi: 10.1002/art.1780270604. [DOI] [PubMed] [Google Scholar]
  5. Böyum A. Isolation of mononuclear cells and granulocytes from human blood. Isolation of monuclear cells by one centrifugation, and of granulocytes by combining centrifugation and sedimentation at 1 g. Scand J Clin Lab Invest Suppl. 1968;97:77–89. [PubMed] [Google Scholar]
  6. Cassatella M. A., Cappelli R., Della Bianca V., Grzeskowiak M., Dusi S., Berton G. Interferon-gamma activates human neutrophil oxygen metabolism and exocytosis. Immunology. 1988 Mar;63(3):499–506. [PMC free article] [PubMed] [Google Scholar]
  7. Coates T. D., Wolach B., Tzeng D. Y., Higgins C., Baehner R. L., Boxer L. A. The mechanism of action of the antiinflammatory agents dexamethasone and Auranofin in human polymorphonuclear leukocytes. Blood. 1983 Nov;62(5):1070–1077. [PubMed] [Google Scholar]
  8. Daimond R. D., Krzesicki R. Mechanisms of attachment of neutrophils to Candida albicans pseudohyphae in the absence of serum, and of subsequent damage to pseudohyphae by microbicidal processes of neutrophils in vitro. J Clin Invest. 1978 Feb;61(2):360–369. doi: 10.1172/JCI108946. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Danley D. L., Hilger A. E. Stimulation of oxidative metabolism in murine polymorphonuclear leukocytes by unopsonized fungal cells: evidence for a mannose-specific mechanism. J Immunol. 1981 Aug;127(2):551–556. [PubMed] [Google Scholar]
  10. Deitch E. A., Bridges R. M. Stress hormones modulate neutrophil and lymphocyte activity in vitro. J Trauma. 1987 Oct;27(10):1146–1154. doi: 10.1097/00005373-198710000-00009. [DOI] [PubMed] [Google Scholar]
  11. Diamond R. D. Inhibition of monocyte-mediated damage to fungal hyphae by steroid hormones. J Infect Dis. 1983 Jan;147(1):160–160. doi: 10.1093/infdis/147.1.160. [DOI] [PubMed] [Google Scholar]
  12. Diamond R. D., Krzesicki R., Epstein B., Jao W. Damage to hyphal forms of fungi by human leukocytes in vitro. A possible host defense mechanism in aspergillosis and mucormycosis. Am J Pathol. 1978 May;91(2):313–328. [PMC free article] [PubMed] [Google Scholar]
  13. Diamond R. D., Lyman C. A., Wysong D. R. Disparate effects of interferon-gamma and tumor necrosis factor-alpha on early neutrophil respiratory burst and fungicidal responses to Candida albicans hyphae in vitro. J Clin Invest. 1991 Feb;87(2):711–720. doi: 10.1172/JCI115050. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Edwards S. W., Say J. E., Hughes V. Gamma interferon enhances the killing of Staphylococcus aureus by human neutrophils. J Gen Microbiol. 1988 Jan;134(1):37–42. doi: 10.1099/00221287-134-1-37. [DOI] [PubMed] [Google Scholar]
  15. Epstein S. M., Verney E., Miale T. D., Sidransky H. Studies on the pathogenesis of experimental pulmonary aspergillosis. Am J Pathol. 1967 Nov;51(5):769–788. [PMC free article] [PubMed] [Google Scholar]
  16. Fleischmann J., Wu-Hsieh B., Howard D. H. The intracellular fate of Histoplasma capsulatum in human macrophages is unaffected by recombinant human interferon-gamma. J Infect Dis. 1990 Jan;161(1):143–145. doi: 10.1093/infdis/161.1.143. [DOI] [PubMed] [Google Scholar]
  17. Gallin J. I., Durocher J. R., Kaplan A. P. Interaction of leukocyte chemotactic factors with the cell surface. I. Chemotactic factor-induced changes in human granulocyte surface charge. J Clin Invest. 1975 May;55(5):967–974. doi: 10.1172/JCI108026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Graham B. S., Tucker W. S., Jr Opportunistic infections in endogenous Cushing's syndrome. Ann Intern Med. 1984 Sep;101(3):334–338. doi: 10.7326/0003-4819-101-3-334. [DOI] [PubMed] [Google Scholar]
  19. Jones C. J., Morris K. J., Jayson M. I. Prednisolone inhibits phagocytosis by polymorphonuclear leucocytes via steroid receptor mediated events. Ann Rheum Dis. 1983 Feb;42(1):56–62. doi: 10.1136/ard.42.1.56. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kasuya Y., Althaus J. R., Freeman J. P., Mitchum R. K., Skelly J. P. Quantitative determination of dexamethasone in human plasma by stable isotope dilution mass spectrometry. J Pharm Sci. 1984 Apr;73(4):446–451. doi: 10.1002/jps.2600730406. [DOI] [PubMed] [Google Scholar]
  21. Kitagawa S., Yuo A., Souza L. M., Saito M., Miura Y., Takaku F. Recombinant human granulocyte colony-stimulating factor enhances superoxide release in human granulocytes stimulated by the chemotactic peptide. Biochem Biophys Res Commun. 1987 May 14;144(3):1143–1146. doi: 10.1016/0006-291x(87)91430-6. [DOI] [PubMed] [Google Scholar]
  22. Klempner M. S., Gallin J. I. Inhibition of neutrophil Fc receptor function by cotricosteroids. Clin Exp Immunol. 1978 Oct;34(1):137–142. [PMC free article] [PubMed] [Google Scholar]
  23. Kurihara A., Ojima F., Tsurufuji S. Chemotactic factor production by rat polymorphonuclear leukocytes: stimulation with opsonized zymosan particles and inhibition by dexamethasone. Biochem Biophys Res Commun. 1984 Mar 15;119(2):720–725. doi: 10.1016/s0006-291x(84)80310-1. [DOI] [PubMed] [Google Scholar]
  24. Levitz S. M., Diamond R. D. A rapid colorimetric assay of fungal viability with the tetrazolium salt MTT. J Infect Dis. 1985 Nov;152(5):938–945. doi: 10.1093/infdis/152.5.938. [DOI] [PubMed] [Google Scholar]
  25. Loose D. S., Schurman D. J., Feldman D. A corticosteroid binding protein and endogenous ligand in C. albicans indicating a possible steroid-receptor system. Nature. 1981 Oct 8;293(5832):477–479. doi: 10.1038/293477a0. [DOI] [PubMed] [Google Scholar]
  26. Loose D. S., Stevens D. A., Schurman D. J., Feldman D. Distribution of a corticosteroid-binding protein in Candida and other fungal genera. J Gen Microbiol. 1983 Aug;129(8):2379–2385. doi: 10.1099/00221287-129-8-2379. [DOI] [PubMed] [Google Scholar]
  27. Lyman C. A., Simons E. R., Melnick D. A., Diamond R. D. Induction of signal transduction in human neutrophils by Candida albicans hyphae: the role of pertussis toxin-sensitive guanosine triphosphate-binding proteins. J Infect Dis. 1988 Nov;158(5):1056–1064. doi: 10.1093/infdis/158.5.1056. [DOI] [PubMed] [Google Scholar]
  28. Lyman C. A., Simons E. R., Melnick D. A., Diamond R. D. Unopsonized Candida albicans hyphae stimulate a neutrophil respiratory burst and a cytosolic calcium flux without membrane depolarization. J Infect Dis. 1987 Nov;156(5):770–776. doi: 10.1093/infdis/156.5.770. [DOI] [PubMed] [Google Scholar]
  29. MacGregor R. R., Spagnuolo P. J., Lentnek A. L. Inhibition of granulocyte adherence by ethanol, prednisone, and aspirin, measured with an assay system. N Engl J Med. 1974 Sep 26;291(13):642–646. doi: 10.1056/NEJM197409262911302. [DOI] [PubMed] [Google Scholar]
  30. Morrison C. J., Brummer E., Isenberg R. A., Stevens D. A. Activation of murine polymorphonuclear neutrophils for fungicidal activity by recombinant gamma interferon. J Leukoc Biol. 1987 May;41(5):434–440. doi: 10.1002/jlb.41.5.434. [DOI] [PubMed] [Google Scholar]
  31. Morstyn G., Lieschke G. J., Sheridan W., Layton J., Cebon J., Fox R. M. Clinical experience with recombinant human granulocyte colony-stimulating factor and granulocyte macrophage colony-stimulating factor. Semin Hematol. 1989 Apr;26(2 Suppl 2):9–13. [PubMed] [Google Scholar]
  32. Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983 Dec 16;65(1-2):55–63. doi: 10.1016/0022-1759(83)90303-4. [DOI] [PubMed] [Google Scholar]
  33. Murray H. W. Interferon-gamma, the activated macrophage, and host defense against microbial challenge. Ann Intern Med. 1988 Apr;108(4):595–608. doi: 10.7326/0003-4819-108-4-595. [DOI] [PubMed] [Google Scholar]
  34. Needs C. J., Smith M., Boutagy J., Donovan S., Cosh D., McCredie M., Brooks P. M. Comparison of methylprednisolone (1 g i.v.) with prednisolone (1 g orally) in rheumatoid arthritis: a pharmacokinetic and clinical study. J Rheumatol. 1988 Feb;15(2):224–228. [PubMed] [Google Scholar]
  35. Parker C. W., Huber M. G., Baumann M. L. Alterations in cyclic AMP metabolism in human bronchial asthma. 3. Leukocyte and lymphocyte responses to steroids. J Clin Invest. 1973 Jun;52(6):1342–1348. doi: 10.1172/JCI107306. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Perussia B., Kobayashi M., Rossi M. E., Anegon I., Trinchieri G. Immune interferon enhances functional properties of human granulocytes: role of Fc receptors and effect of lymphotoxin, tumor necrosis factor, and granulocyte-macrophage colony-stimulating factor. J Immunol. 1987 Feb 1;138(3):765–774. [PubMed] [Google Scholar]
  37. Petroni K. C., Shen L., Guyre P. M. Modulation of human polymorphonuclear leukocyte IgG Fc receptors and Fc receptor-mediated functions by IFN-gamma and glucocorticoids. J Immunol. 1988 May 15;140(10):3467–3472. [PubMed] [Google Scholar]
  38. Polak-Wyss A. Protective effect of human granulocyte colony-stimulating factor (hG-CSF) on Cryptococcus and Aspergillus infections in normal and immunosuppressed mice. Mycoses. 1991 May-Jun;34(5-6):205–215. doi: 10.1111/j.1439-0507.1991.tb00645.x. [DOI] [PubMed] [Google Scholar]
  39. Rex J. H., Bennett J. E., Gallin J. I., Malech H. L., DeCarlo E. S., Melnick D. A. In vivo interferon-gamma therapy augments the in vitro ability of chronic granulomatous disease neutrophils to damage Aspergillus hyphae. J Infect Dis. 1991 Apr;163(4):849–852. doi: 10.1093/infdis/163.4.849. [DOI] [PubMed] [Google Scholar]
  40. Rex J. H., Bennett J. E., Gallin J. I., Malech H. L., Melnick D. A. Normal and deficient neutrophils can cooperate to damage Aspergillus fumigatus hyphae. J Infect Dis. 1990 Aug;162(2):523–528. doi: 10.1093/infdis/162.2.523. [DOI] [PubMed] [Google Scholar]
  41. Roilides E., Mertins S., Eddy J., Walsh T. J., Pizzo P. A., Rubin M. Impairment of neutrophil chemotactic and bactericidal function in children infected with human immunodeficiency virus type 1 and partial reversal after in vitro exposure to granulocyte-macrophage colony-stimulating factor. J Pediatr. 1990 Oct;117(4):531–540. doi: 10.1016/s0022-3476(05)80684-5. [DOI] [PubMed] [Google Scholar]
  42. Roilides E., Walsh T. J., Pizzo P. A., Rubin M. Granulocyte colony-stimulating factor enhances the phagocytic and bactericidal activity of normal and defective human neutrophils. J Infect Dis. 1991 Mar;163(3):579–583. doi: 10.1093/infdis/163.3.579. [DOI] [PubMed] [Google Scholar]
  43. Roth J. A., Kaeberle M. L. Effects of in vivo dexamethasone administration on in vitro bovine polymorphonuclear leukocyte function. Infect Immun. 1981 Aug;33(2):434–441. doi: 10.1128/iai.33.2.434-441.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Schaffner A., Douglas H., Braude A. Selective protection against conidia by mononuclear and against mycelia by polymorphonuclear phagocytes in resistance to Aspergillus. Observations on these two lines of defense in vivo and in vitro with human and mouse phagocytes. J Clin Invest. 1982 Mar;69(3):617–631. doi: 10.1172/JCI110489. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Schaffner A. Therapeutic concentrations of glucocorticoids suppress the antimicrobial activity of human macrophages without impairing their responsiveness to gamma interferon. J Clin Invest. 1985 Nov;76(5):1755–1764. doi: 10.1172/JCI112166. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Shalaby M. R., Aggarwal B. B., Rinderknecht E., Svedersky L. P., Finkle B. S., Palladino M. A., Jr Activation of human polymorphonuclear neutrophil functions by interferon-gamma and tumor necrosis factors. J Immunol. 1985 Sep;135(3):2069–2073. [PubMed] [Google Scholar]
  47. Sheridan W. P., Morstyn G., Wolf M., Dodds A., Lusk J., Maher D., Layton J. E., Green M. D., Souza L., Fox R. M. Granulocyte colony-stimulating factor and neutrophil recovery after high-dose chemotherapy and autologous bone marrow transplantation. Lancet. 1989 Oct 14;2(8668):891–895. doi: 10.1016/s0140-6736(89)91552-3. [DOI] [PubMed] [Google Scholar]
  48. Szefler S. J., Norton C. E., Ball B., Gross J. M., Aida Y., Pabst M. J. IFN-gamma and LPS overcome glucocorticoid inhibition of priming for superoxide release in human monocytes. Evidence that secretion of IL-1 and tumor necrosis factor-alpha is not essential for monocyte priming. J Immunol. 1989 Jun 1;142(11):3985–3992. [PubMed] [Google Scholar]
  49. Umeki S., Soejima R. Hydrocortisone inhibits the respiratory burst oxidase from human neutrophils in whole-cell and cell-free systems. Biochim Biophys Acta. 1990 Apr 9;1052(1):211–215. doi: 10.1016/0167-4889(90)90078-r. [DOI] [PubMed] [Google Scholar]
  50. Wajszczuk C. P., Dummer J. S., Ho M., Van Thiel D. H., Starzl T. E., Iwatsuki S., Shaw B., Jr Fungal infections in liver transplant recipients. Transplantation. 1985 Oct;40(4):347–353. doi: 10.1097/00007890-198510000-00002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Waldorf A. R., Levitz S. M., Diamond R. D. In vivo bronchoalveolar macrophage defense against Rhizopus oryzae and Aspergillus fumigatus. J Infect Dis. 1984 Nov;150(5):752–760. doi: 10.1093/infdis/150.5.752. [DOI] [PubMed] [Google Scholar]
  52. Walsh T. J. Invasive pulmonary aspergillosis in patients with neoplastic diseases. Semin Respir Infect. 1990 Jun;5(2):111–122. [PubMed] [Google Scholar]
  53. Walsh T. J., Mendelsohn G. Invasive aspergillosis complicating Cushing's syndrome. Arch Intern Med. 1981 Aug;141(9):1227–1228. [PubMed] [Google Scholar]
  54. Warren M. K., Vogel S. N. Opposing effects of glucocorticoids on interferon-gamma-induced murine macrophage Fc receptor and Ia antigen expression. J Immunol. 1985 Apr;134(4):2462–2469. [PubMed] [Google Scholar]
  55. Webel M. L., Ritts R. E., Jr, Taswell H. F., Danadio J. V., Jr, Woods J. E. Cellular immunity after intravenous administration of methylprednisolone. J Lab Clin Med. 1974 Mar;83(3):383–392. [PubMed] [Google Scholar]
  56. Weinberger M., Elattar I., Marshall D., Steinberg S. M., Redner R. L., Young N. S., Pizzo P. A. Patterns of infection in patients with aplastic anemia and the emergence of Aspergillus as a major cause of death. Medicine (Baltimore) 1992 Jan;71(1):24–43. doi: 10.1097/00005792-199201000-00003. [DOI] [PubMed] [Google Scholar]
  57. Welch W. D., Devlin P. Hydrocortisone sodium succinate reversibly inhibits human neutrophil oxidative activity at clinically relevant concentrations. Chem Biol Interact. 1983 Feb;43(2):239–244. doi: 10.1016/0009-2797(83)90098-4. [DOI] [PubMed] [Google Scholar]

Articles from Infection and Immunity are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES