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. 1992 Oct;60(10):4003–4008. doi: 10.1128/iai.60.10.4003-4008.1992

Tumor necrosis factor and interleukin-6 in Candida albicans infection in normal and granulocytopenic mice.

S Steinshamn 1, A Waage 1
PMCID: PMC257429  PMID: 1398912

Abstract

We administered a neutralizing monoclonal antibody to tumor necrosis factor (TNF) during infection with Candida albicans in normal and granulocytopenic mice. Mice were rendered granulocytopenic (less than 0.1 x 10(9) granulocytes per liter) with cyclophosphamide. Growth of C. albicans from the kidneys was significantly increased in normal mice treated with the antibody to TNF, compared with that in control mice, after 36 h (3.6 x 10(4) +/- 1.2 x 10(4) CFU per kidney versus 9.1 x 10(3) +/- 6.2 x 10(3) CFU per kidney; P less than 0.05) and after 72 h (3.7 x 10(6) +/- 2.7 x 10(6) CFU per kidney versus 2.3 x 10(4) +/- 1.3 x 10(4) CFU per kidney; P less than 0.01). In granulocytopenic mice, the antibody to TNF had no effect on the growth of C. albicans from the kidneys. Furthermore, our study showed that the cytokines TNF and interleukin-6 (IL-6) were produced in a dose-dependent manner during C. albicans infection. TNF was detectable between 6 and 60 h, with peak levels at 24 h. Both TNF and IL-6 levels were significantly higher in cyclophosphamide-treated mice than in normal mice. Heat-inactivated C. albicans induced a TNF response different from that induced by viable C. albicans, with an early peak occurring at 3 to 4 h and declining to non-detectable levels after 15 to 24 h. Peak levels of TNF obtained with heat-inactivated C. albicans were lower than those obtained with viable C. albicans. Our study demonstrates that TNF and IL-6 are produced systemically during C. albicans infection and suggests that TNF is essential for granulocyte antifungal activity in vivo.

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  1. Aarden L. A., De Groot E. R., Schaap O. L., Lansdorp P. M. Production of hybridoma growth factor by human monocytes. Eur J Immunol. 1987 Oct;17(10):1411–1416. doi: 10.1002/eji.1830171004. [DOI] [PubMed] [Google Scholar]
  2. Bodey G. P. Candidiasis in cancer patients. Am J Med. 1984 Oct 30;77(4D):13–19. [PubMed] [Google Scholar]
  3. Chensue S. W., Terebuh P. D., Remick D. G., Scales W. E., Kunkel S. L. In vivo biologic and immunohistochemical analysis of interleukin-1 alpha, beta and tumor necrosis factor during experimental endotoxemia. Kinetics, Kupffer cell expression, and glucocorticoid effects. Am J Pathol. 1991 Feb;138(2):395–402. [PMC free article] [PubMed] [Google Scholar]
  4. 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]
  5. Djeu J. Y., Blanchard D. K., Halkias D., Friedman H. Growth inhibition of Candida albicans by human polymorphonuclear neutrophils: activation by interferon-gamma and tumor necrosis factor. J Immunol. 1986 Nov 1;137(9):2980–2984. [PubMed] [Google Scholar]
  6. Djeu J. Y., Blanchard D. K., Richards A. L., Friedman H. Tumor necrosis factor induction by Candida albicans from human natural killer cells and monocytes. J Immunol. 1988 Dec 1;141(11):4047–4052. [PubMed] [Google Scholar]
  7. Djeu J. Y., Serbousek D., Blanchard D. K. Release of tumor necrosis factor by human polymorphonuclear leukocytes. Blood. 1990 Oct 1;76(7):1405–1409. [PubMed] [Google Scholar]
  8. Espevik T., Nissen-Meyer J. A highly sensitive cell line, WEHI 164 clone 13, for measuring cytotoxic factor/tumor necrosis factor from human monocytes. J Immunol Methods. 1986 Dec 4;95(1):99–105. doi: 10.1016/0022-1759(86)90322-4. [DOI] [PubMed] [Google Scholar]
  9. Ferrante A. Tumor necrosis factor alpha potentiates neutrophil antimicrobial activity: increased fungicidal activity against Torulopsis glabrata and Candida albicans and associated increases in oxygen radical production and lysosomal enzyme release. Infect Immun. 1989 Jul;57(7):2115–2122. doi: 10.1128/iai.57.7.2115-2122.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Havell E. A. Evidence that tumor necrosis factor has an important role in antibacterial resistance. J Immunol. 1989 Nov 1;143(9):2894–2899. [PubMed] [Google Scholar]
  11. Havell E. A. Production of tumor necrosis factor during murine listeriosis. J Immunol. 1987 Dec 15;139(12):4225–4231. [PubMed] [Google Scholar]
  12. Havell E. A., Sehgal P. B. Tumor necrosis factor-independent IL-6 production during murine listeriosis. J Immunol. 1991 Jan 15;146(2):756–761. [PubMed] [Google Scholar]
  13. Helle M., Brakenhoff J. P., De Groot E. R., Aarden L. A. Interleukin 6 is involved in interleukin 1-induced activities. Eur J Immunol. 1988 Jun;18(6):957–959. doi: 10.1002/eji.1830180619. [DOI] [PubMed] [Google Scholar]
  14. Horn R., Wong B., Kiehn T. E., Armstrong D. Fungemia in a cancer hospital: changing frequency, earlier onset, and results of therapy. Rev Infect Dis. 1985 Sep-Oct;7(5):646–655. doi: 10.1093/clinids/7.5.646. [DOI] [PubMed] [Google Scholar]
  15. Hurtrel B., Lagrange P. H., Michel J. C. Systemic candidiasis in mice. I.--Correlation between kidney infection and mortality rate. Ann Immunol (Paris) 1980 Jan-Feb;131C(1):93–104. [PubMed] [Google Scholar]
  16. Hurtrel B., Lagrange P. H., Michel J. C. Systemic candidiasis in mice. II.--Main role of polymorphonuclear leukocytes in resistance to infection. Ann Immunol (Paris) 1980 Jan-Feb;131C(1):105–118. [PubMed] [Google Scholar]
  17. Kullberg B. J., van 't Wout J. W., van Furth R. Role of granulocytes in increased host resistance to Candida albicans induced by recombinant interleukin-1. Infect Immun. 1990 Oct;58(10):3319–3324. doi: 10.1128/iai.58.10.3319-3324.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. 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]
  19. Nakamura S., Minami A., Fujimoto K., Kojima T. Combination effect of recombinant human interleukin-1 alpha with antimicrobial agents. Antimicrob Agents Chemother. 1989 Oct;33(10):1804–1810. doi: 10.1128/aac.33.10.1804. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Nakane A., Minagawa T., Kato K. Endogenous tumor necrosis factor (cachectin) is essential to host resistance against Listeria monocytogenes infection. Infect Immun. 1988 Oct;56(10):2563–2569. doi: 10.1128/iai.56.10.2563-2569.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. North R. J. Cyclophosphamide-facilitated adoptive immunotherapy of an established tumor depends on elimination of tumor-induced suppressor T cells. J Exp Med. 1982 Apr 1;155(4):1063–1074. doi: 10.1084/jem.155.4.1063. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Opal S. M., Cross A. S., Kelly N. M., Sadoff J. C., Bodmer M. W., Palardy J. E., Victor G. H. Efficacy of a monoclonal antibody directed against tumor necrosis factor in protecting neutropenic rats from lethal infection with Pseudomonas aeruginosa. J Infect Dis. 1990 Jun;161(6):1148–1152. doi: 10.1093/infdis/161.6.1148. [DOI] [PubMed] [Google Scholar]
  23. Pecyk R. A., Fraser-Smith E. B., Matthews T. R. Efficacy of interleukin-1 beta against systemic Candida albicans infections in normal and immunosuppressed mice. Infect Immun. 1989 Oct;57(10):3257–3258. doi: 10.1128/iai.57.10.3257-3258.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Riipi L., Carlson E. Tumor necrosis factor (TNF) is induced in mice by Candida albicans: role of TNF in fibrinogen increase. Infect Immun. 1990 Sep;58(9):2750–2754. doi: 10.1128/iai.58.9.2750-2754.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Rogers T., Balish E. Experimental Candida albicans infection in conventional mice and germfree rats. Infect Immun. 1976 Jul;14(1):33–38. doi: 10.1128/iai.14.1.33-38.1976. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Sabbele N. R., Van Oudenaren A., Benner R. The effect of cyclophosphamide on B cells and 'background' immunoglobulin-secreting cells in mice. Immunopharmacology. 1988 Jan-Feb;15(1):21–30. doi: 10.1016/0162-3109(88)90039-2. [DOI] [PubMed] [Google Scholar]
  27. 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]
  28. Sheehan K. C., Ruddle N. H., Schreiber R. D. Generation and characterization of hamster monoclonal antibodies that neutralize murine tumor necrosis factors. J Immunol. 1989 Jun 1;142(11):3884–3893. [PubMed] [Google Scholar]
  29. Starnes H. F., Jr, Pearce M. K., Tewari A., Yim J. H., Zou J. C., Abrams J. S. Anti-IL-6 monoclonal antibodies protect against lethal Escherichia coli infection and lethal tumor necrosis factor-alpha challenge in mice. J Immunol. 1990 Dec 15;145(12):4185–4191. [PubMed] [Google Scholar]
  30. Tracey K. J., Beutler B., Lowry S. F., Merryweather J., Wolpe S., Milsark I. W., Hariri R. J., Fahey T. J., 3rd, Zentella A., Albert J. D. Shock and tissue injury induced by recombinant human cachectin. Science. 1986 Oct 24;234(4775):470–474. doi: 10.1126/science.3764421. [DOI] [PubMed] [Google Scholar]
  31. Tracey K. J., Fong Y., Hesse D. G., Manogue K. R., Lee A. T., Kuo G. C., Lowry S. F., Cerami A. Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature. 1987 Dec 17;330(6149):662–664. doi: 10.1038/330662a0. [DOI] [PubMed] [Google Scholar]
  32. Van't Wout J. W., Van der Meer J. W., Barza M., Dinarello C. A. Protection of neutropenic mice from lethal Candida albicans infection by recombinant interleukin 1. Eur J Immunol. 1988 Jul;18(7):1143–1146. doi: 10.1002/eji.1830180728. [DOI] [PubMed] [Google Scholar]
  33. Vecchiarelli A., Cenci E., Puliti M., Blasi E., Puccetti P., Cassone A., Bistoni F. Protective immunity induced by low-virulence Candida albicans: cytokine production in the development of the anti-infectious state. Cell Immunol. 1989 Dec;124(2):334–344. doi: 10.1016/0008-8749(89)90135-4. [DOI] [PubMed] [Google Scholar]
  34. Waage A., Brandtzaeg P., Halstensen A., Kierulf P., Espevik T. The complex pattern of cytokines in serum from patients with meningococcal septic shock. Association between interleukin 6, interleukin 1, and fatal outcome. J Exp Med. 1989 Jan 1;169(1):333–338. doi: 10.1084/jem.169.1.333. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Waage A., Halstensen A., Espevik T. Association between tumour necrosis factor in serum and fatal outcome in patients with meningococcal disease. Lancet. 1987 Feb 14;1(8529):355–357. doi: 10.1016/s0140-6736(87)91728-4. [DOI] [PubMed] [Google Scholar]
  36. van der Meer J. W., Barza M., Wolff S. M., Dinarello C. A. A low dose of recombinant interleukin 1 protects granulocytopenic mice from lethal gram-negative infection. Proc Natl Acad Sci U S A. 1988 Mar;85(5):1620–1623. doi: 10.1073/pnas.85.5.1620. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. von Asmuth E. J., Maessen J. G., van der Linden C. J., Buurman W. A. Tumour necrosis factor alpha (TNF-alpha) and interleukin 6 in a zymosan-induced shock model. Scand J Immunol. 1990 Oct;32(4):313–319. doi: 10.1111/j.1365-3083.1990.tb02925.x. [DOI] [PubMed] [Google Scholar]

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