Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1996 Apr 1;183(4):1345–1355. doi: 10.1084/jem.183.4.1345

Impaired neutrophil response and CD4+ T helper cell 1 development in interleukin 6-deficient mice infected with Candida albicans

PMCID: PMC2192497  PMID: 8666893

Abstract

To define the role of interleukin (IL)6 in Candida albicans infection, IL-6 deficient mice were assessed for susceptibility to systemic or gastrointestinal infection, as well as for parameters of elicited T helper cell (Th) immunity. IL-6-deficient mice were more susceptible than wild-type mice to either type of infection caused by virulent C. albicans. In response to systemic challenge with a live vaccine strain of yeast, IL-6-deficient mice failed to mount Th1-associated protective immunity, but the resulting Th2-biased response could be redirected to the Th1 phenotype by IL-10 neutralization. Severe impairment of the macrophage and neutrophil response to infection was observed in IL-6- deficient mice, but administration of IL-6 would increase both neutrophil response and resistance to infection. IL-6 seems to oppose the Th2-promoting role of IL-10 in candidiasis, its early regulatory activity involving effects on neutrophil function.

Full Text

The Full Text of this article is available as a PDF (1.9 MB).

Selected References

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

  1. Appelberg R., Castro A. G., Pedrosa J., Minóprio P. Role of interleukin-6 in the induction of protective T cells during mycobacterial infections in mice. Immunology. 1994 Jul;82(3):361–364. [PMC free article] [PubMed] [Google Scholar]
  2. Arcone R., Pucci P., Zappacosta F., Fontaine V., Malorni A., Marino G., Ciliberto G. Single-step purification and structural characterization of human interleukin-6 produced in Escherichia coli from a T7 RNA polymerase expression vector. Eur J Biochem. 1991 Jun 15;198(3):541–547. doi: 10.1111/j.1432-1033.1991.tb16048.x. [DOI] [PubMed] [Google Scholar]
  3. Beagley K. W., Eldridge J. H., Lee F., Kiyono H., Everson M. P., Koopman W. J., Hirano T., Kishimoto T., McGhee J. R. Interleukins and IgA synthesis. Human and murine interleukin 6 induce high rate IgA secretion in IgA-committed B cells. J Exp Med. 1989 Jun 1;169(6):2133–2148. doi: 10.1084/jem.169.6.2133. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Birx D. L., Redfield R. R., Tencer K., Fowler A., Burke D. S., Tosato G. Induction of interleukin-6 during human immunodeficiency virus infection. Blood. 1990 Dec 1;76(11):2303–2310. [PubMed] [Google Scholar]
  5. Borish L., Rosenbaum R., Albury L., Clark S. Activation of neutrophils by recombinant interleukin 6. Cell Immunol. 1989 Jul;121(2):280–289. doi: 10.1016/0008-8749(89)90026-9. [DOI] [PubMed] [Google Scholar]
  6. Breen E. C., Rezai A. R., Nakajima K., Beall G. N., Mitsuyasu R. T., Hirano T., Kishimoto T., Martinez-Maza O. Infection with HIV is associated with elevated IL-6 levels and production. J Immunol. 1990 Jan 15;144(2):480–484. [PubMed] [Google Scholar]
  7. Cantorna M. T., Balish E. Mucosal and systemic candidiasis in congenitally immunodeficient mice. Infect Immun. 1990 Apr;58(4):1093–1100. doi: 10.1128/iai.58.4.1093-1100.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cenci E., Mencacci A., Spaccapelo R., Tonnetti L., Mosci P., Enssle K. H., Puccetti P., Romani L., Bistoni F. T helper cell type 1 (Th1)- and Th2-like responses are present in mice with gastric candidiasis but protective immunity is associated with Th1 development. J Infect Dis. 1995 May;171(5):1279–1288. doi: 10.1093/infdis/171.5.1279. [DOI] [PubMed] [Google Scholar]
  9. Cenci E., Romani L., Mencacci A., Spaccapelo R., Schiaffella E., Puccetti P., Bistoni F. Interleukin-4 and interleukin-10 inhibit nitric oxide-dependent macrophage killing of Candida albicans. Eur J Immunol. 1993 May;23(5):1034–1038. doi: 10.1002/eji.1830230508. [DOI] [PubMed] [Google Scholar]
  10. 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]
  11. Cohen R., Roth F. J., Delgado E., Ahearn D. G., Kalser M. H. Fungal flora of the normal human small and large intestine. N Engl J Med. 1969 Mar 20;280(12):638–641. doi: 10.1056/NEJM196903202801204. [DOI] [PubMed] [Google Scholar]
  12. Cole G. T., Lynn K. T., Seshan K. R., Pope L. M. Gastrointestinal and systemic candidosis in immunocompromised mice. J Med Vet Mycol. 1989;27(6):363–380. doi: 10.1080/02681218980000491. [DOI] [PubMed] [Google Scholar]
  13. D'Andrea A., Aste-Amezaga M., Valiante N. M., Ma X., Kubin M., Trinchieri G. Interleukin 10 (IL-10) inhibits human lymphocyte interferon gamma-production by suppressing natural killer cell stimulatory factor/IL-12 synthesis in accessory cells. J Exp Med. 1993 Sep 1;178(3):1041–1048. doi: 10.1084/jem.178.3.1041. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Dalrymple S. A., Lucian L. A., Slattery R., McNeil T., Aud D. M., Fuchino S., Lee F., Murray R. Interleukin-6-deficient mice are highly susceptible to Listeria monocytogenes infection: correlation with inefficient neutrophilia. Infect Immun. 1995 Jun;63(6):2262–2268. doi: 10.1128/iai.63.6.2262-2268.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Fattori E., Cappelletti M., Costa P., Sellitto C., Cantoni L., Carelli M., Faggioni R., Fantuzzi G., Ghezzi P., Poli V. Defective inflammatory response in interleukin 6-deficient mice. J Exp Med. 1994 Oct 1;180(4):1243–1250. doi: 10.1084/jem.180.4.1243. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Frei K., Malipiero U. V., Leist T. P., Zinkernagel R. M., Schwab M. E., Fontana A. On the cellular source and function of interleukin 6 produced in the central nervous system in viral diseases. Eur J Immunol. 1989 Apr;19(4):689–694. doi: 10.1002/eji.1830190418. [DOI] [PubMed] [Google Scholar]
  17. 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]
  18. Heremans H., Dillen C., Put W., Van Damme J., Billiau A. Protective effect of anti-interleukin (IL)-6 antibody against endotoxin, associated with paradoxically increased IL-6 levels. Eur J Immunol. 1992 Sep;22(9):2395–2401. doi: 10.1002/eji.1830220932. [DOI] [PubMed] [Google Scholar]
  19. Horii Y., Muraguchi A., Iwano M., Matsuda T., Hirayama T., Yamada H., Fujii Y., Dohi K., Ishikawa H., Ohmoto Y. Involvement of IL-6 in mesangial proliferative glomerulonephritis. J Immunol. 1989 Dec 15;143(12):3949–3955. [PubMed] [Google Scholar]
  20. Hsieh C. S., Macatonia S. E., O'Garra A., Murphy K. M. T cell genetic background determines default T helper phenotype development in vitro. J Exp Med. 1995 Feb 1;181(2):713–721. doi: 10.1084/jem.181.2.713. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kopf M., Baumann H., Freer G., Freudenberg M., Lamers M., Kishimoto T., Zinkernagel R., Bluethmann H., Köhler G. Impaired immune and acute-phase responses in interleukin-6-deficient mice. Nature. 1994 Mar 24;368(6469):339–342. doi: 10.1038/368339a0. [DOI] [PubMed] [Google Scholar]
  22. Libert C., Takahashi N., Cauwels A., Brouckaert P., Bluethmann H., Fiers W. Response of interleukin-6-deficient mice to tumor necrosis factor-induced metabolic changes and lethality. Eur J Immunol. 1994 Sep;24(9):2237–2242. doi: 10.1002/eji.1830240945. [DOI] [PubMed] [Google Scholar]
  23. Liu Z., Simpson R. J., Cheers C. Recombinant interleukin-6 protects mice against experimental bacterial infection. Infect Immun. 1992 Oct;60(10):4402–4406. doi: 10.1128/iai.60.10.4402-4406.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Liu Z., Simpson R. J., Cheers C. Role of IL-6 in activation of T cells for acquired cellular resistance to Listeria monocytogenes. J Immunol. 1994 Jun 1;152(11):5375–5380. [PubMed] [Google Scholar]
  25. Morawetz R. A., Doherty T. M., Giese N. A., Hartley J. W., Müller W., Kühn R., Rajewsky K., Coffman R., Morse H. C., 3rd Resistance to murine acquired immunodeficiency syndrome (MAIDS) Science. 1994 Jul 8;265(5169):264–267. doi: 10.1126/science.8023146. [DOI] [PubMed] [Google Scholar]
  26. Poli V., Balena R., Fattori E., Markatos A., Yamamoto M., Tanaka H., Ciliberto G., Rodan G. A., Costantini F. Interleukin-6 deficient mice are protected from bone loss caused by estrogen depletion. EMBO J. 1994 Mar 1;13(5):1189–1196. doi: 10.1002/j.1460-2075.1994.tb06368.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Puccetti P., Mencacci A., Cenci E., Spaccapelo R., Mosci P., Enssle K. H., Romani L., Bistoni F. Cure of murine candidiasis by recombinant soluble interleukin-4 receptor. J Infect Dis. 1994 Jun;169(6):1325–1331. doi: 10.1093/infdis/169.6.1325. [DOI] [PubMed] [Google Scholar]
  28. Puccetti P., Romani L., Bistoni F. A TH1-TH2-like switch in candidiasis: new perspectives for therapy. Trends Microbiol. 1995 Jun;3(6):237–240. doi: 10.1016/s0966-842x(00)88931-3. [DOI] [PubMed] [Google Scholar]
  29. Ramsay A. J., Husband A. J., Ramshaw I. A., Bao S., Matthaei K. I., Koehler G., Kopf M. The role of interleukin-6 in mucosal IgA antibody responses in vivo. Science. 1994 Apr 22;264(5158):561–563. doi: 10.1126/science.8160012. [DOI] [PubMed] [Google Scholar]
  30. Robertson E., Bradley A., Kuehn M., Evans M. Germ-line transmission of genes introduced into cultured pluripotential cells by retroviral vector. Nature. 1986 Oct 2;323(6087):445–448. doi: 10.1038/323445a0. [DOI] [PubMed] [Google Scholar]
  31. Romani L., Cenci E., Mencacci A., Spaccapelo R., Grohmann U., Puccetti P., Bistoni F. Gamma interferon modifies CD4+ subset expression in murine candidiasis. Infect Immun. 1992 Nov;60(11):4950–4952. doi: 10.1128/iai.60.11.4950-4952.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Romani L., Mencacci A., Cenci E., Spaccapelo R., Mosci P., Puccetti P., Bistoni F. CD4+ subset expression in murine candidiasis. Th responses correlate directly with genetically determined susceptibility or vaccine-induced resistance. J Immunol. 1993 Feb 1;150(3):925–931. [PubMed] [Google Scholar]
  33. Romani L., Mencacci A., Grohmann U., Mocci S., Mosci P., Puccetti P., Bistoni F. Neutralizing antibody to interleukin 4 induces systemic protection and T helper type 1-associated immunity in murine candidiasis. J Exp Med. 1992 Jul 1;176(1):19–25. doi: 10.1084/jem.176.1.19. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Romani L., Mencacci A., Tonnetti L., Spaccapelo R., Cenci E., Puccetti P., Wolf S. F., Bistoni F. IL-12 is both required and prognostic in vivo for T helper type 1 differentiation in murine candidiasis. J Immunol. 1994 Dec 1;153(11):5167–5175. [PubMed] [Google Scholar]
  35. Romani L., Mencacci A., Tonnetti L., Spaccapelo R., Cenci E., Wolf S., Puccetti P., Bistoni F. Interleukin-12 but not interferon-gamma production correlates with induction of T helper type-1 phenotype in murine candidiasis. Eur J Immunol. 1994 Apr;24(4):909–915. doi: 10.1002/eji.1830240419. [DOI] [PubMed] [Google Scholar]
  36. Romani L., Puccetti P., Bistoni F. Biological role of Th cell subsets in candidiasis. Chem Immunol. 1996;63:115–137. [PubMed] [Google Scholar]
  37. Romani L., Puccetti P., Mencacci A., Cenci E., Spaccapelo R., Tonnetti L., Grohmann U., Bistoni F. Neutralization of IL-10 up-regulates nitric oxide production and protects susceptible mice from challenge with Candida albicans. J Immunol. 1994 Apr 1;152(7):3514–3521. [PubMed] [Google Scholar]
  38. Rousset F., Garcia E., Defrance T., Péronne C., Vezzio N., Hsu D. H., Kastelein R., Moore K. W., Banchereau J. Interleukin 10 is a potent growth and differentiation factor for activated human B lymphocytes. Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1890–1893. doi: 10.1073/pnas.89.5.1890. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Saiki R. K., Scharf S., Faloona F., Mullis K. B., Horn G. T., Erlich H. A., Arnheim N. Enzymatic amplification of beta-globin genomic sequences and restriction site analysis for diagnosis of sickle cell anemia. Science. 1985 Dec 20;230(4732):1350–1354. doi: 10.1126/science.2999980. [DOI] [PubMed] [Google Scholar]
  40. Scott P. Selective differentiation of CD4+ T helper cell subsets. Curr Opin Immunol. 1993 Jun;5(3):391–397. doi: 10.1016/0952-7915(93)90058-z. [DOI] [PubMed] [Google Scholar]
  41. Screpanti I., Romani L., Musiani P., Modesti A., Fattori E., Lazzaro D., Sellitto C., Scarpa S., Bellavia D., Lattanzio G. Lymphoproliferative disorder and imbalanced T-helper response in C/EBP beta-deficient mice. EMBO J. 1995 May 1;14(9):1932–1941. doi: 10.1002/j.1460-2075.1995.tb07185.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Spaccapelo R., Romani L., Tonnetti L., Cenci E., Mencacci A., Del Sero G., Tognellini R., Reed S. G., Puccetti P., Bistoni F. TGF-beta is important in determining the in vivo patterns of susceptibility or resistance in mice infected with Candida albicans. J Immunol. 1995 Aug 1;155(3):1349–1360. [PubMed] [Google Scholar]
  43. 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]
  44. Steinshamn S., Waage A. Tumor necrosis factor and interleukin-6 in Candida albicans infection in normal and granulocytopenic mice. Infect Immun. 1992 Oct;60(10):4003–4008. doi: 10.1128/iai.60.10.4003-4008.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Suzuki Y., Yang Q., Conley F. K., Abrams J. S., Remington J. S. Antibody against interleukin-6 reduces inflammation and numbers of cysts in brains of mice with toxoplasmic encephalitis. Infect Immun. 1994 Jul;62(7):2773–2778. doi: 10.1128/iai.62.7.2773-2778.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Taga T., Kishimoto T. Cytokine receptors and signal transduction. FASEB J. 1992 Dec;6(15):3387–3396. doi: 10.1096/fasebj.6.15.1334470. [DOI] [PubMed] [Google Scholar]
  47. Tonnetti L., Spaccapelo R., Cenci E., Mencacci A., Puccetti P., Coffman R. L., Bistoni F., Romani L. Interleukin-4 and -10 exacerbate candidiasis in mice. Eur J Immunol. 1995 Jun;25(6):1559–1565. doi: 10.1002/eji.1830250614. [DOI] [PubMed] [Google Scholar]
  48. Ulich T. R., Guo K. Z., Remick D., del Castillo J., Yin S. M. Endotoxin-induced cytokine gene expression in vivo. III. IL-6 mRNA and serum protein expression and the in vivo hematologic effects of IL-6. J Immunol. 1991 Apr 1;146(7):2316–2323. [PubMed] [Google Scholar]
  49. Van Snick J., Cayphas S., Vink A., Uyttenhove C., Coulie P. G., Rubira M. R., Simpson R. J. Purification and NH2-terminal amino acid sequence of a T-cell-derived lymphokine with growth factor activity for B-cell hybridomas. Proc Natl Acad Sci U S A. 1986 Dec;83(24):9679–9683. doi: 10.1073/pnas.83.24.9679. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Van Snick J. Interleukin-6: an overview. Annu Rev Immunol. 1990;8:253–278. doi: 10.1146/annurev.iy.08.040190.001345. [DOI] [PubMed] [Google Scholar]
  51. Wong G. G., Witek-Giannotti J. S., Temple P. A., Kriz R., Ferenz C., Hewick R. M., Clark S. C., Ikebuchi K., Ogawa M. Stimulation of murine hemopoietic colony formation by human IL-6. J Immunol. 1988 May 1;140(9):3040–3044. [PubMed] [Google Scholar]
  52. Yoshimoto T., Nakanishi K., Hirose S., Hiroishi K., Okamura H., Takemoto Y., Kanamaru A., Hada T., Tamura T., Kakishita E. High serum IL-6 level reflects susceptible status of the host to endotoxin and IL-1/tumor necrosis factor. J Immunol. 1992 Jun 1;148(11):3596–3603. [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES