Abstract
Protective immunity against Brucella abortus is mediated by acquired cellular resistance, with gamma interferon (IFN-gamma)-producing T cells playing a key role. Interleukin-12 (IL-12) is a cytokine that has a profound effect on the induction of IFN-gamma-producing Th1 and NK cells. Here we report that depletion of endogenous IL-12 before infection of mice significantly exacerbated brucella infection. IL-12-depleted mice also had reduced splenomegaly resulting from infection and showed a decrease in percentage and absolute numbers of macrophages compared with those in control infected mice. Furthermore, spleen cells from IL-12-depleted mice had a reduced ability to produce nitrite, a product of activated macrophages. This could be the result of the low production of IFN-gamma by splenic T cells observed in the IL-12-depleted mice. The mechanism whereby IL-12 controls antibacterial resistance is discussed.
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- Bancroft G. J., Sheehan K. C., Schreiber R. D., Unanue E. R. Tumor necrosis factor is involved in the T cell-independent pathway of macrophage activation in scid mice. J Immunol. 1989 Jul 1;143(1):127–130. [PubMed] [Google Scholar]
- Cheers C., Pavlov H., Riglar C., Madraso E. Macrophage activation during experimental murine brucellosis. III. Do macrophages exert feedback control during brucellosis? Cell Immunol. 1980 Jan;49(1):168–177. doi: 10.1016/0008-8749(80)90066-0. [DOI] [PubMed] [Google Scholar]
- Fortier A. H., Polsinelli T., Green S. J., Nacy C. A. Activation of macrophages for destruction of Francisella tularensis: identification of cytokines, effector cells, and effector molecules. Infect Immun. 1992 Mar;60(3):817–825. doi: 10.1128/iai.60.3.817-825.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Havell E. A. Purification and further characterization of an anti-murine interferon-gamma monoclonal neutralizing antibody. J Interferon Res. 1986 Oct;6(5):489–497. doi: 10.1089/jir.1986.6.489. [DOI] [PubMed] [Google Scholar]
- 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]
- Jacobsen S. E., Veiby O. P., Smeland E. B. Cytotoxic lymphocyte maturation factor (interleukin 12) is a synergistic growth factor for hematopoietic stem cells. J Exp Med. 1993 Aug 1;178(2):413–418. doi: 10.1084/jem.178.2.413. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Murphy J. W., McDaniel D. O. In vitro reactivity of natural killer (NK) cells against Cryptococcus neoformans. J Immunol. 1982 Apr;128(4):1577–1583. [PubMed] [Google Scholar]
- Ploemacher R. E., van Soest P. L., Boudewijn A., Neben S. Interleukin-12 enhances interleukin-3 dependent multilineage hematopoietic colony formation stimulated by interleukin-11 or steel factor. Leukemia. 1993 Sep;7(9):1374–1380. [PubMed] [Google Scholar]
- Reynolds D. S., Boom W. H., Abbas A. K. Inhibition of B lymphocyte activation by interferon-gamma. J Immunol. 1987 Aug 1;139(3):767–773. [PubMed] [Google Scholar]
- Stuehr D. J., Marletta M. A. Induction of nitrite/nitrate synthesis in murine macrophages by BCG infection, lymphokines, or interferon-gamma. J Immunol. 1987 Jul 15;139(2):518–525. [PubMed] [Google Scholar]
- 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]
- 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]
- Tripp C. S., Wolf S. F., Unanue E. R. Interleukin 12 and tumor necrosis factor alpha are costimulators of interferon gamma production by natural killer cells in severe combined immunodeficiency mice with listeriosis, and interleukin 10 is a physiologic antagonist. Proc Natl Acad Sci U S A. 1993 Apr 15;90(8):3725–3729. doi: 10.1073/pnas.90.8.3725. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zhan Y., Cheers C. Endogenous gamma interferon mediates resistance to Brucella abortus infection. Infect Immun. 1993 Nov;61(11):4899–4901. doi: 10.1128/iai.61.11.4899-4901.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zhan Y., Kelso A., Cheers C. Cytokine production in the murine response to brucella infection or immunization with antigenic extracts. Immunology. 1993 Nov;80(3):458–464. [PMC free article] [PubMed] [Google Scholar]
- Zhan Y., Kelso A., Cheers C. Differential activation of Brucella-reactive CD4+ T cells by Brucella infection or immunization with antigenic extracts. Infect Immun. 1995 Mar;63(3):969–975. doi: 10.1128/iai.63.3.969-975.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]