1887

Abstract

By using mice with a targetted disruption in the gene encoding inducible nitric-oxide synthase (iNOS), we have studied the role of nitric oxide (NO) in lymphocytic choriomeningitis virus (LCMV)-induced, T cell-mediated protective immunity and immunopathology. The afferent phase of the T cell-mediated immune response was found to be unaltered in iNOS-deficient mice compared with wild-type C57BL/6 mice, and LCMV- induced general immunosuppression was equally pronounced in both strains. analysis revealed identical kinetics of virus clearance, as well as unaltered clinical severity of systemic LCMV infection in both strains. Concerning the outcome of intracerebral infection, no significant differences were found between iNOS-deficient and wild-type mice in the number or composition of mononuclear cells found in the cerebrospinal fluid on day 6 post-infection. Likewise, NO did not influence the up-regulation of proinflammatory cytokine/chemokine genes significantly, nor did it influence the development of fatal meningitis. However, a reduced virus-specific delayed-type hypersensitivity reaction was observed in iNOS-deficient mice compared with both IFN-γ-deficient and wild-type mice. This might suggest a role of NO in regulating vascular reactivity in the context of T cell-mediated inflammation. In conclusion, these findings indicate a minimal role for iNOS/NO in the host response to LCMV. Except for a reduced local oedema in the knockout mice, iNOS/NO seems to be redundant in controlling both the afferent and efferent phases of the T cell-mediated immune response to LCMV infection.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/0022-1317-80-11-2997
1999-11-01
2024-03-28
Loading full text...

Full text loading...

/deliver/fulltext/jgv/80/11/0802997a.html?itemId=/content/journal/jgv/10.1099/0022-1317-80-11-2997&mimeType=html&fmt=ahah

References

  1. Adler H., Beland J. L., Del-Pan N. C., Kobzik L., Brewer J. P., Martin T. R., Rimm I. J. 1997; Suppression of herpes simplex virus type 1 (HSV-1)-induced pneumonia in mice by inhibition of inducible nitric oxide synthase (iNOS, NOS2). Journal of Experimental Medicine 185:1533–1540
    [Google Scholar]
  2. Akaike T., Noguchi Y., Ijiri S., Setoguchi K., Suga M., Zheng Y. M., Dietzschold B., Maeda H. 1996; Pathogenesis of influenza virus- induced pneumonia: involvement of both nitric oxide and oxygen radicals. Proceedings of the National Academy of Sciences USA: 93:2448–2453
    [Google Scholar]
  3. Albina J. E., Abate J. A., Henry W. L. Jr 1991; Nitric oxide production is required for murine resident peritoneal macrophages to suppress mitogen-stimulated T cell proliferation. Role of IFN-gamma in the induction of the nitric oxide-synthesizing pathway. Journal of Immunology 147:144–148
    [Google Scholar]
  4. Andersson E. C., Christensen J. P., Scheynius A., Marker O., Thomsen A. R. 1995; Lymphocytic choriomeningitis virus infection is associated with long-standing perturbation of LFA-1 expression on CD8+ T cells. Scandinavian Journal of Immunology 42:110–118
    [Google Scholar]
  5. Bogdan C. 1997; Of microbes, macrophages and nitric oxide. Behring Institute Mitteilungen58–72
    [Google Scholar]
  6. Bogdan C. 1998; The multiplex function of nitric oxide in (auto)immunity. Journal of Experimental Medicine 187:1361–1365
    [Google Scholar]
  7. Butz E. A., Hostager B. S., Southern P. J. 1994; Macrophages in mice acutely infected with lymphocytic choriomeningitis virus are primed for nitric oxide synthesis. Microbial Pathogenesis 16:283–295
    [Google Scholar]
  8. Campbell I. L. 1996; Exacerbation of lymphocytic choriomeningitis in mice treated with the inducible nitric oxide synthase inhibitor aminoguanidine. Journal of Neuroimmunology 71:31–36
    [Google Scholar]
  9. Campbell I. L., Hobbs M. V., Kemper P., Oldstone M. B. 1994a; Cerebral expression of multiple cytokine genes in mice with lymphocytic choriomeningitis. Journal of Immunology 152:716–723
    [Google Scholar]
  10. Campbell I. L., Samimi A., Chiang C. S. 1994b; Expression of the inducible nitric oxide synthase. Correlation with neuropathology and clinical features in mice with lymphocytic choriomeningitis. Journal of Immunology 153:3622–3629
    [Google Scholar]
  11. Christensen J. P., Stenvang J. P., Marker O., Thomsen A. R. 1996; Characterization of virus-primed CD8+ T cells with a type 1 cytokine profile. International Immunology 8:1453–1461
    [Google Scholar]
  12. Corbett J. A., Mikhael A., Shimizu J., Frederick K., Misko T. P., McDaniel M. L., Kanagawa O., Unanue E. R. 1993; Nitric oxide production in islets from nonobese diabetic mice: aminoguanidine- sensitive and -resistant stages in the immunological diabetic process. Proceedings of the National Academy of Sciences USA: 90:8992–8995
    [Google Scholar]
  13. Croen K. D. 1993; Evidence for antiviral effect of nitric oxide. Inhibition of herpes simplex virus type 1 replication. Journal of Clinical Investigation 91:2446–2452
    [Google Scholar]
  14. Diefenbach A., Schindler H., Donhauser N., Lorenz E., Laskay T. M., MacMicking J., Rollinghoff M., Gresser I., Bogdan C. 1998; Type 1 interferon (IFNα/β) and type 2 nitric oxide synthase regulate the innate immune response to a protozoan parasite. Immunity 8:77–87
    [Google Scholar]
  15. Doherty P. C., Allan J. E., Lynch F., Ceredig R. 1990; Dissection of an inflammatory process induced by CD8+ T cells. Immunology Today 11:55–59
    [Google Scholar]
  16. Fang F. C. 1997; Perspectives series: host/pathogen interactions. Mechanisms of nitric oxide-related antimicrobial activity. Journal of Clinical Investigation 99:2818–2825
    [Google Scholar]
  17. Fehsel K., Kroncke K. D., Meyer K. L., Huber H., Wahn V., Kolb-Bachofen V. 1995; Nitric oxide induces apoptosis in mouse thymocytes. Journal of Immunology 155:2858–2865
    [Google Scholar]
  18. Frei K., Leist T. P., Meager A., Gallo P., Leppert D., Zinkernagel R. M., Fontana A. 1988; Production of B cell stimulatory factor-2 and interferon gamma in the central nervous system during viral meningitis and encephalitis. Evaluation in a murine model infection and in patients. Journal of Experimental Medicine 168:449–453
    [Google Scholar]
  19. Green I. C., Cunningham J. M., Delaney C. A., Elphick M. R., Mabley J. G., Green M. H. 1994; Effects of cytokines and nitric oxide donors on insulin secretion, cyclic GMP and DNA damage: relation to nitric oxide production. Biochemical Society Transactions 22:30–37
    [Google Scholar]
  20. Hoffman R. A., Langrehr J. M., Billiar T. R., Curran R. D., Simmons R. L. 1990; Alloantigen-induced activation of rat splenocytes is regulated by the oxidative metabolism of l-arginine. Journal of Immunology 145:2220–2226
    [Google Scholar]
  21. Iadecola C., Zhang F., Xu X. 1995; Inhibition of inducible nitric oxide synthase ameliorates cerebral ischemic damage. American Journal of Physiology 268:R286–R292
    [Google Scholar]
  22. Iadecola C., Zhang F., Casey R., Nagayama M., Ross M. E. 1997; Delayed reduction of ischemic brain injury and neurological deficits in mice lacking the inducible nitric oxide synthase gene. Journal of Neuroscience 17:9157–9164
    [Google Scholar]
  23. Kagi D., Ledermann B., Burki K., Seiler P., Odermatt B., Olsen K. J., Podack E. R., Zinkernagel R. M., Hengartner H. 1994; Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin-deficient mice. Nature 369:31–37
    [Google Scholar]
  24. Karupiah G., Xie Q. W., Buller R. M., Nathan C., Duarte C., MacMicking J. D. 1993; Inhibition of viral replication by interferon-gamma-induced nitric oxide synthase. Science 261:1445–1448
    [Google Scholar]
  25. Karupiah G., Chen J. H., Nathan C. F., Mahalingam S., MacMicking J. D. 1998a; Identification of nitric oxide synthase 2 as an innate resistance locus against ectromelia virus infection. Journal of Virology 72:7703–7706
    [Google Scholar]
  26. Karupiah G., Chen J. H., Mahalingam S., Nathan C. F., MacMicking J. D. 1998b; Rapid interferon gamma-dependent clearance of influenza A virus and protection from consolidating pneumonitis in nitric oxide synthase 2-deficient mice. Journal of Experimental Medicine 188:1541–1546
    [Google Scholar]
  27. Kolb H., Kolb-Bachofen V. 1998; Nitric oxide in autoimmune disease: cytotoxic or regulatory mediator?. Immunology Today 19:556–561
    [Google Scholar]
  28. Laubach V. E., Shesely E. G., Smithies O., Sherman P. A. 1995; Mice lacking inducible nitric oxide synthase are not resistant to lipopolysaccharide- induced death. Proceedings of the National Academy of Sciences USA: 92:10688–10692
    [Google Scholar]
  29. Lohman B. L., Welsh R. M. 1998; Apoptotic regulation of T cells and absence of immune deficiency in virus-infected gamma interferon receptor knockout mice. Journal of Virology 72:7815–7821
    [Google Scholar]
  30. MacLean A., Wei X.-Q., Huang F.-P., Al-Alem U. A. H., Chan W. L., Liew F. Y. 1998; Mice lacking inducible nitric-oxide synthase are more susceptible to herpes simplex virus infection despite enhanced Th1 cell responses. Journal of General Virology 79:825–830
    [Google Scholar]
  31. MacMicking J. D., Nathan C., Hom G., Chartrain N., Fletcher D. S., Trumbauer M., Stevens K., Xie Q. W., Sokol K., Hutchinson N. and others 1995; Altered responses to bacterial infection and endotoxic shock in mice lacking inducible nitric oxide synthase. Cell 81:641–650
    [Google Scholar]
  32. MacMicking J., Xie Q. W., Nathan C. 1997; Nitric oxide and macrophage function. Annual Review of Immunology 15:323–350
    [Google Scholar]
  33. Marker O., Volkert M. 1973; Studies on cell-mediated immunity to lymphocytic choriomeningitis virus in mice. Journal of Experimental Medicine 137:1511–1525
    [Google Scholar]
  34. Marker O., Scheynius A., Christensen J. P., Thomsen A. R. 1995; Virus-activated T cells regulate expression of adhesion molecules on endothelial cells in sites of infection. Journal of Neuroimmunology 62:35–42
    [Google Scholar]
  35. Nansen A., Christensen J. P., Ropke C., Marker O., Scheynius A., Thomsen A. R. 1998; Role of interferon- gamma in the pathogenesis of LCMV-induced meningitis: unimpaired leucocyte recruitment, but deficient macrophage activation in interferon-gamma knock-out mice. Journal of Neuroimmunology 86:202–212
    [Google Scholar]
  36. Okuda Y., Sakoda S., Shimaoka M., Yanagihara T. 1996; Nitric oxide induces apoptosis in mouse splenic T lymphocytes. Immunology Letters 52:135–138
    [Google Scholar]
  37. Peng H. B., Spiecker M., Liao J. K. 1998; Inducible nitric oxide: an autoregulatory feedback inhibitor of vascular inflammation. Journal of Immunology 161:1970–1976
    [Google Scholar]
  38. Razvi E. S., Welsh R. M. 1993; Programmed cell death of T lymphocytes during acute viral infection: a mechanism for virus- induced immune deficiency. Journal of Virology 67:5754–5765
    [Google Scholar]
  39. Ross R., Gillitzer C., Kleinz R., Schwing J., Kleinert H., Forstermann U., Reske-Kunz A. B. 1998; Involvement of NO in contact hypersensitivity. International Immunology 10:61–69
    [Google Scholar]
  40. Taylor-Robinson A. W., Liew F. Y., Severn A., Xu D., McSorley S. J., Garside P., Padron J., Phillips R. S. 1994; Regulation of the immune response by nitric oxide differentially produced by T helper type 1 and T helper type 2 cells. European Journal of Immunology 24:980–984
    [Google Scholar]
  41. Thomsen A. R., Marker O. 1989; MHC and non-MHC genes regulate elimination of lymphocytic choriomeningitis virus and antiviral cytotoxic T lymphocyte and delayed-type hypersensitivity mediating T lymphocyte activity in parallel. Journal of Immunology 142:1333–1341
    [Google Scholar]
  42. Wei X. Q., Charles I. G., Smith A., Ure J., Feng G. J., Huang F. P., Xu D., Muller W., Moncada S., Liew F. Y. 1995; Altered immune responses in mice lacking inducible nitric oxide synthase. Nature 375:408–411
    [Google Scholar]
  43. Xie K., Dong Z., Fidler I. J. 1996; Activation of nitric oxide synthase gene for inhibition of cancer metastasis. Journal of Leukocyte Biology 59:797–803
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/0022-1317-80-11-2997
Loading
/content/journal/jgv/10.1099/0022-1317-80-11-2997
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error