Skip to main content
NCBI home page
Immunology logoLink to Immunology
. 1996 Mar;87(3):467–474. doi: 10.1046/j.1365-2567.1996.492569.x

Retrovirus-elicited interleukin-12 and tumour necrosis factor-alpha as inducers of interferon-gamma-mediated pathology in mouse AIDS.

N A Giese 1, R T Gazzinelli 1, J K Actor 1, R A Morawetz 1, M Sarzotti 1, H C Morse 3rd 1
PMCID: PMC1384118  PMID: 8778035

Abstract

Spleen cells from mice resistant or sensitive to mouse acquired immune deficiency syndrome (MAIDS) were examined for cytokine mRNA. In MAIDS-resistant BALB/c mice, cytokine transcripts peaked at 1 week after infection with Type 1 cytokines [interleukin-2 (IL-2), tumour necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), IL-12], dominating over Type 2 cytokines (IL-4, IL-10). Expression of cytokines other than IL-2 later declined to levels seen in uninfected mice. In MAIDS-sensitive B6 mice, transcripts for all cytokines were increased at 1 week and, except for IL-2, increased progressively. Spontaneous production of IFN-gamma protein was associated with enhanced mRNA expression at 1 week after infection of either strain, but none was detectable in association with even higher levels of transcripts at later times after infection of B6 mice. Spleen cells from longer-term-infected B6 mice, however, produced substantial amounts of IFN-gamma following treatment with lipopolysaccharide (LPS) or IL-12. Inclusion of anti-IL-12 or anti-TNF-alpha antibodies blocked induction of IFN-gamma by LPS. Induction of IFN-gamma by IL-12 was potentiated by TNF-alpha following stimulation of intact spleen cells and purified CD4+ or CD8+ T cells, as well as negatively selected CD4-8- cells from infected B6 mice. Further studies showed that IFN-gamma knockout mice on a B6 background developed MAIDS with a prolonged time-course, whereas BALB/c knockout mice were unchanged in their resistance to MAIDS. These studies suggest that continuing low-level expression of IFN-gamma, stimulated by IL-12 and TNF-alpha, contributes to the susceptibility of B6 mice to MAIDS but is not required for the resistance of BALB/c mice to disease.

Full text

PDF
467

Images in this article

469Figure 1
on p.469
470Figure 2
on p.470
471Figure 4
on p.471
472Figure 5
on p.472
472Figure 6
on p.472

Selected References

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

  1. Barral-Netto M., da Silva J. S., Barral A., Reed S. Up-regulation of T helper 2 and down-regulation of T helper 1 cytokines during murine retrovirus-induced immunodeficiency syndrome enhances susceptibility of a resistant mouse strain to Leishmania amazonensis. Am J Pathol. 1995 Mar;146(3):635–642. [PMC free article] [PubMed] [Google Scholar]
  2. Chattopadhyay S. K., Morse H. C., 3rd, Makino M., Ruscetti S. K., Hartley J. W. Defective virus is associated with induction of murine retrovirus-induced immunodeficiency syndrome. Proc Natl Acad Sci U S A. 1989 May;86(10):3862–3866. doi: 10.1073/pnas.86.10.3862. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Cheung S. C., Chattopadhyay S. K., Morse H. C., 3rd, Pitha P. M. Expression of defective virus and cytokine genes in murine AIDS. J Virol. 1991 Feb;65(2):823–828. doi: 10.1128/jvi.65.2.823-828.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Cloyd M. W., Hartley J. W., Rowe W. P. Lymphomagenicity of recombinant mink cell focus-inducing murine leukemia viruses. J Exp Med. 1980 Mar 1;151(3):542–552. doi: 10.1084/jem.151.3.542. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Dalton D. K., Pitts-Meek S., Keshav S., Figari I. S., Bradley A., Stewart T. A. Multiple defects of immune cell function in mice with disrupted interferon-gamma genes. Science. 1993 Mar 19;259(5102):1739–1742. doi: 10.1126/science.8456300. [DOI] [PubMed] [Google Scholar]
  6. Doherty T. M., Morse H. C., 3rd, Coffman R. L. Modulation of specific T cell responses by concurrent infection with Leishmania major and LP-BM5 murine leukemia viruses. Int Immunol. 1995 Jan;7(1):131–138. doi: 10.1093/intimm/7.1.131. [DOI] [PubMed] [Google Scholar]
  7. Gazzinelli R. T., Eltoum I., Wynn T. A., Sher A. Acute cerebral toxoplasmosis is induced by in vivo neutralization of TNF-alpha and correlates with the down-regulated expression of inducible nitric oxide synthase and other markers of macrophage activation. J Immunol. 1993 Oct 1;151(7):3672–3681. [PubMed] [Google Scholar]
  8. Gazzinelli R. T., Giese N. A., Morse H. C., 3rd In vivo treatment with interleukin 12 protects mice from immune abnormalities observed during murine acquired immunodeficiency syndrome (MAIDS). J Exp Med. 1994 Dec 1;180(6):2199–2208. doi: 10.1084/jem.180.6.2199. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Gazzinelli R. T., Hartley J. W., Fredrickson T. N., Chattopadhyay S. K., Sher A., Morse H. C., 3rd Opportunistic infections and retrovirus-induced immunodeficiency: studies of acute and chronic infections with Toxoplasma gondii in mice infected with LP-BM5 murine leukemia viruses. Infect Immun. 1992 Oct;60(10):4394–4401. doi: 10.1128/iai.60.10.4394-4401.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. 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]
  11. Gazzinelli R. T., Makino M., Chattopadhyay S. K., Snapper C. M., Sher A., Hügin A. W., Morse H. C., 3rd CD4+ subset regulation in viral infection. Preferential activation of Th2 cells during progression of retrovirus-induced immunodeficiency in mice. J Immunol. 1992 Jan 1;148(1):182–188. [PubMed] [Google Scholar]
  12. Hartley J. W., Fredrickson T. N., Yetter R. A., Makino M., Morse H. C., 3rd Retrovirus-induced murine acquired immunodeficiency syndrome: natural history of infection and differing susceptibility of inbred mouse strains. J Virol. 1989 Mar;63(3):1223–1231. doi: 10.1128/jvi.63.3.1223-1231.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hügin A. W., Cerny A., Morse H. C., 3rd Mice with an acquired immunodeficiency (MAIDS) develop a persistent infection after injection with Listeria monocytogenes. Cell Immunol. 1994 Apr 15;155(1):246–252. doi: 10.1006/cimm.1994.1117. [DOI] [PubMed] [Google Scholar]
  14. Ishida H., Hastings R., Kearney J., Howard M. Continuous anti-interleukin 10 antibody administration depletes mice of Ly-1 B cells but not conventional B cells. J Exp Med. 1992 May 1;175(5):1213–1220. doi: 10.1084/jem.175.5.1213. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Jolicoeur P. Murine acquired immunodeficiency syndrome (MAIDS): an animal model to study the AIDS pathogenesis. FASEB J. 1991 Jul;5(10):2398–2405. doi: 10.1096/fasebj.5.10.2065888. [DOI] [PubMed] [Google Scholar]
  16. Kühn R., Löhler J., Rennick D., Rajewsky K., Müller W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell. 1993 Oct 22;75(2):263–274. doi: 10.1016/0092-8674(93)80068-p. [DOI] [PubMed] [Google Scholar]
  17. Makino M., Morse H. C., 3rd, Fredrickson T. N., Hartley J. W. H-2-associated and background genes influence the development of a murine retrovirus-induced immunodeficiency syndrome. J Immunol. 1990 Jun 1;144(11):4347–4355. [PubMed] [Google Scholar]
  18. Makino M., Winkler D. F., Wunderlich J., Hartley J. W., Morse H. C., Holmes K. L. High expression of NK-1.1 antigen is induced by infection with murine AIDS virus. Immunology. 1993 Oct;80(2):319–325. [PMC free article] [PubMed] [Google Scholar]
  19. 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]
  20. Morse H. C., 3rd, Chattopadhyay S. K., Makino M., Fredrickson T. N., Hügin A. W., Hartley J. W. Retrovirus-induced immunodeficiency in the mouse: MAIDS as a model for AIDS. AIDS. 1992 Jul;6(7):607–621. doi: 10.1097/00002030-199207000-00001. [DOI] [PubMed] [Google Scholar]
  21. Morse H. C., 3rd, Giese N., Morawetz R., Tang Y., Gazzinelli R., Kim W. K., Chattopadhyay S., Hartley J. W. Cells and cytokines in the pathogenesis of MAIDS, a retrovirus-induced immunodeficiency syndrome of mice. Springer Semin Immunopathol. 1995;17(2-3):231–245. doi: 10.1007/BF00196167. [DOI] [PubMed] [Google Scholar]
  22. Mosmann T. R., Fong T. A. Specific assays for cytokine production by T cells. J Immunol Methods. 1989 Jan 17;116(2):151–158. doi: 10.1016/0022-1759(89)90198-1. [DOI] [PubMed] [Google Scholar]
  23. Muralidhar G., Koch S., Haas M., Swain S. L. CD4 T cells in murine acquired immunodeficiency syndrome: polyclonal progression to anergy. J Exp Med. 1992 Jun 1;175(6):1589–1599. doi: 10.1084/jem.175.6.1589. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Pitha P. M., Biegel D., Yetter R. A., Morse H. C., 3rd Abnormal regulation of IFN-alpha, -beta, and -gamma expression in MAIDS, a murine retrovirus-induced immunodeficiency syndrome. J Immunol. 1988 Nov 15;141(10):3611–3616. [PubMed] [Google Scholar]
  25. Rowe W. P., Pugh W. E., Hartley J. W. Plaque assay techniques for murine leukemia viruses. Virology. 1970 Dec;42(4):1136–1139. doi: 10.1016/0042-6822(70)90362-4. [DOI] [PubMed] [Google Scholar]
  26. Schall T. J., O'Hehir R. E., Goeddel D. V., Lamb J. R. Uncoupling of cytokine mRNA expression and protein secretion during the induction phase of T cell anergy. J Immunol. 1992 Jan 15;148(2):381–387. [PubMed] [Google Scholar]
  27. Schoenhaut D. S., Chua A. O., Wolitzky A. G., Quinn P. M., Dwyer C. M., McComas W., Familletti P. C., Gately M. K., Gubler U. Cloning and expression of murine IL-12. J Immunol. 1992 Jun 1;148(11):3433–3440. [PubMed] [Google Scholar]
  28. Svetić A., Finkelman F. D., Jian Y. C., Dieffenbach C. W., Scott D. E., McCarthy K. F., Steinberg A. D., Gause W. C. Cytokine gene expression after in vivo primary immunization with goat antibody to mouse IgD antibody. J Immunol. 1991 Oct 1;147(7):2391–2397. [PubMed] [Google Scholar]
  29. 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]
  30. Uehara S., Hitoshi Y., Numata F., Makino M., Howard M., Mizuochi T., Takatsu K. An IFN-gamma-dependent pathway plays a critical role in the pathogenesis of murine immunodeficiency syndrome induced by LP-BM5 murine leukemia virus. Int Immunol. 1994 Dec;6(12):1937–1947. doi: 10.1093/intimm/6.12.1937. [DOI] [PubMed] [Google Scholar]
  31. Wang Y., Ardestani S. K., Liang B., Beckham C., Watson R. R. Anti-IL-4 monoclonal antibody and IFN-gamma administration retards development of immune dysfunction and cytokine dysregulation during murine AIDS. Immunology. 1994 Nov;83(3):384–389. [PMC free article] [PubMed] [Google Scholar]

Articles from Immunology are provided here courtesy of British Society for Immunology

RESOURCES