Skip to main content
Infection and Immunity logoLink to Infection and Immunity
. 1996 Apr;64(4):1437–1440. doi: 10.1128/iai.64.4.1437-1440.1996

Endogenous and exogenous interleukin-12 augment the protective immune response in mice orally challenged with Salmonella dublin.

T Kincy-Cain 1, J D Clements 1, K L Bost 1
PMCID: PMC173939  PMID: 8606114

Abstract

Following oral challenge with Salmonella dublin, we observed significant increases in interleukin-12 (IL-12) protein expression in the mesenteric lymph nodes. The importance of this endogenous cytokine production in the immune response against S. dublin was demonstrated by in vivo depletion of IL-12 with an anti-IL-12 monoclonal antibody prior to oral S. dublin challenge. Mice pretreated with anti-IL-12 antibody had increased salmonellosis and reduced survival times compared with mice receiving control antibody. Furthermore, administration of exogenous murine recombinant IL-12 dramatically increased survival times of mice challenged orally with S. dublin. Together, these results demonstrate that endogenous and exogenous IL-12 significantly augment the mucosal immune response against the intracellular pathogen S. dublin.

Full Text

The Full Text of this article is available as a PDF (181.6 KB).

Selected References

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

  1. Afonso L. C., Scharton T. M., Vieira L. Q., Wysocka M., Trinchieri G., Scott P. The adjuvant effect of interleukin-12 in a vaccine against Leishmania major. Science. 1994 Jan 14;263(5144):235–237. doi: 10.1126/science.7904381. [DOI] [PubMed] [Google Scholar]
  2. Biron C. A., Gazzinelli R. T. Effects of IL-12 on immune responses to microbial infections: a key mediator in regulating disease outcome. Curr Opin Immunol. 1995 Aug;7(4):485–496. doi: 10.1016/0952-7915(95)80093-x. [DOI] [PubMed] [Google Scholar]
  3. Bost K. L., Clements J. D. In vivo induction of interleukin-12 mRNA expression after oral immunization with Salmonella dublin or the B subunit of Escherichia coli heat-labile enterotoxin. Infect Immun. 1995 Mar;63(3):1076–1083. doi: 10.1128/iai.63.3.1076-1083.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chong C., Bost K. L., Clements J. D. Differential production of interleukin-12 mRNA by murine macrophages in response to viable or killed Salmonella spp. Infect Immun. 1996 Apr;64(4):1154–1160. doi: 10.1128/iai.64.4.1154-1160.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cooper A. M., Roberts A. D., Rhoades E. R., Callahan J. E., Getzy D. M., Orme I. M. The role of interleukin-12 in acquired immunity to Mycobacterium tuberculosis infection. Immunology. 1995 Mar;84(3):423–432. [PMC free article] [PubMed] [Google Scholar]
  6. Flynn J. L., Goldstein M. M., Triebold K. J., Sypek J., Wolf S., Bloom B. R. IL-12 increases resistance of BALB/c mice to Mycobacterium tuberculosis infection. J Immunol. 1995 Sep 1;155(5):2515–2524. [PubMed] [Google Scholar]
  7. Gazzinelli R. T., Hieny S., Wynn T. A., Wolf S., Sher A. Interleukin 12 is required for the T-lymphocyte-independent induction of interferon gamma by an intracellular parasite and induces resistance in T-cell-deficient hosts. Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):6115–6119. doi: 10.1073/pnas.90.13.6115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Gubler U., Chua A. O., Schoenhaut D. S., Dwyer C. M., McComas W., Motyka R., Nabavi N., Wolitzky A. G., Quinn P. M., Familletti P. C. Coexpression of two distinct genes is required to generate secreted bioactive cytotoxic lymphocyte maturation factor. Proc Natl Acad Sci U S A. 1991 May 15;88(10):4143–4147. doi: 10.1073/pnas.88.10.4143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Heinzel F. P., Schoenhaut D. S., Rerko R. M., Rosser L. E., Gately M. K. Recombinant interleukin 12 cures mice infected with Leishmania major. J Exp Med. 1993 May 1;177(5):1505–1509. doi: 10.1084/jem.177.5.1505. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Hsieh C. S., Macatonia S. E., Tripp C. S., Wolf S. F., O'Garra A., Murphy K. M. Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science. 1993 Apr 23;260(5107):547–549. doi: 10.1126/science.8097338. [DOI] [PubMed] [Google Scholar]
  11. Hsu H. S. Pathogenesis and immunity in murine salmonellosis. Microbiol Rev. 1989 Dec;53(4):390–409. doi: 10.1128/mr.53.4.390-409.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hunter C. A., Subauste C. S., Van Cleave V. H., Remington J. S. Production of gamma interferon by natural killer cells from Toxoplasma gondii-infected SCID mice: regulation by interleukin-10, interleukin-12, and tumor necrosis factor alpha. Infect Immun. 1994 Jul;62(7):2818–2824. doi: 10.1128/iai.62.7.2818-2824.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Khan I. A., Matsuura T., Kasper L. H. Interleukin-12 enhances murine survival against acute toxoplasmosis. Infect Immun. 1994 May;62(5):1639–1642. doi: 10.1128/iai.62.5.1639-1642.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kobayashi M., Fitz L., Ryan M., Hewick R. M., Clark S. C., Chan S., Loudon R., Sherman F., Perussia B., Trinchieri G. Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. J Exp Med. 1989 Sep 1;170(3):827–845. doi: 10.1084/jem.170.3.827. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Manetti R., Gerosa F., Giudizi M. G., Biagiotti R., Parronchi P., Piccinni M. P., Sampognaro S., Maggi E., Romagnani S., Trinchieri G. Interleukin 12 induces stable priming for interferon gamma (IFN-gamma) production during differentiation of human T helper (Th) cells and transient IFN-gamma production in established Th2 cell clones. J Exp Med. 1994 Apr 1;179(4):1273–1283. doi: 10.1084/jem.179.4.1273. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Manetti R., Parronchi P., Giudizi M. G., Piccinni M. P., Maggi E., Trinchieri G., Romagnani S. Natural killer cell stimulatory factor (interleukin 12 [IL-12]) induces T helper type 1 (Th1)-specific immune responses and inhibits the development of IL-4-producing Th cells. J Exp Med. 1993 Apr 1;177(4):1199–1204. doi: 10.1084/jem.177.4.1199. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Mattner F., Fischer S., Guckes S., Jin S., Kaulen H., Schmitt E., Rüde E., Germann T. The interleukin-12 subunit p40 specifically inhibits effects of the interleukin-12 heterodimer. Eur J Immunol. 1993 Sep;23(9):2202–2208. doi: 10.1002/eji.1830230923. [DOI] [PubMed] [Google Scholar]
  18. Murray H. W., Hariprashad J. Interleukin 12 is effective treatment for an established systemic intracellular infection: experimental visceral leishmaniasis. J Exp Med. 1995 Jan 1;181(1):387–391. doi: 10.1084/jem.181.1.387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Orange J. S., Wolf S. F., Biron C. A. Effects of IL-12 on the response and susceptibility to experimental viral infections. J Immunol. 1994 Feb 1;152(3):1253–1264. [PubMed] [Google Scholar]
  20. Ramarathinam L., Niesel D. W., Klimpel G. R. Salmonella typhimurium induces IFN-gamma production in murine splenocytes. Role of natural killer cells and macrophages. J Immunol. 1993 May 1;150(9):3973–3981. [PubMed] [Google Scholar]
  21. Schijns V. E., Haagmans B. L., Horzinek M. C. IL-12 stimulates an antiviral type 1 cytokine response but lacks adjuvant activity in IFN-gamma-receptor-deficient mice. J Immunol. 1995 Sep 1;155(5):2525–2532. [PubMed] [Google Scholar]
  22. Scott P. IL-12: initiation cytokine for cell-mediated immunity. Science. 1993 Apr 23;260(5107):496–497. doi: 10.1126/science.8097337. [DOI] [PubMed] [Google Scholar]
  23. Seder R. A., Gazzinelli R., Sher A., Paul W. E. Interleukin 12 acts directly on CD4+ T cells to enhance priming for interferon gamma production and diminishes interleukin 4 inhibition of such priming. Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):10188–10192. doi: 10.1073/pnas.90.21.10188. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Stern A. S., Podlaski F. J., Hulmes J. D., Pan Y. C., Quinn P. M., Wolitzky A. G., Familletti P. C., Stremlo D. L., Truitt T., Chizzonite R. Purification to homogeneity and partial characterization of cytotoxic lymphocyte maturation factor from human B-lymphoblastoid cells. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6808–6812. doi: 10.1073/pnas.87.17.6808. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Sypek J. P., Chung C. L., Mayor S. E., Subramanyam J. M., Goldman S. J., Sieburth D. S., Wolf S. F., Schaub R. G. Resolution of cutaneous leishmaniasis: interleukin 12 initiates a protective T helper type 1 immune response. J Exp Med. 1993 Jun 1;177(6):1797–1802. doi: 10.1084/jem.177.6.1797. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Tripp C. S., Gately M. K., Hakimi J., Ling P., Unanue E. R. Neutralization of IL-12 decreases resistance to Listeria in SCID and C.B-17 mice. Reversal by IFN-gamma. J Immunol. 1994 Feb 15;152(4):1883–1887. [PubMed] [Google Scholar]
  27. Vieira L. Q., Hondowicz B. D., Afonso L. C., Wysocka M., Trinchieri G., Scott P. Infection with Leishmania major induces interleukin-12 production in vivo. Immunol Lett. 1994 May;40(2):157–161. doi: 10.1016/0165-2478(94)90187-2. [DOI] [PubMed] [Google Scholar]
  28. Wolf S. F., Temple P. A., Kobayashi M., Young D., Dicig M., Lowe L., Dzialo R., Fitz L., Ferenz C., Hewick R. M. Cloning of cDNA for natural killer cell stimulatory factor, a heterodimeric cytokine with multiple biologic effects on T and natural killer cells. J Immunol. 1991 May 1;146(9):3074–3081. [PubMed] [Google Scholar]
  29. Wysocka M., Kubin M., Vieira L. Q., Ozmen L., Garotta G., Scott P., Trinchieri G. Interleukin-12 is required for interferon-gamma production and lethality in lipopolysaccharide-induced shock in mice. Eur J Immunol. 1995 Mar;25(3):672–676. doi: 10.1002/eji.1830250307. [DOI] [PubMed] [Google Scholar]
  30. Zhan Y., Cheers C. Endogenous interleukin-12 is involved in resistance to Brucella abortus infection. Infect Immun. 1995 Apr;63(4):1387–1390. doi: 10.1128/iai.63.4.1387-1390.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES