Abstract
The roles of the inflammatory cytokines tumour necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1) and IL-12, in murine cytomegalovirus (MCMV) disease were investigated in susceptible BALB/c and resistant C57BL/6 mice. MCMV infection induced IL-1 and TNF-alpha production by peritoneal cells from BALB/c mice, as demonstrated previously in C57BL/6 mice. Overt ill-health and viral replication in the spleens of BALB/c mice were increased by in vivo treatment with soluble TNF-alpha receptors to inhibit the activity of this cytokine, whilst antibodies to IL-12 had a similar but more restricted effect C57BL/6 mice were not affected by either treatment, suggesting TNF-alpha and IL-12 are not critical for natural killer cell-mediated restriction of viral replication in the spleen. Soluble TNF-alpha receptors and antibodies to IL-12 also enhanced MCMV titres and numbers of viral antigen-positive cells in the livers of BALB/c mice and TNF-alpha receptors have similar effects in C57BL/6 livers. In contrast, IL-1 receptors improved the health of MCMV-infected BALB/c mice and reduced viral replication and hepatitis at some time-points. Mechanisms which may underlie these changes are discussed.
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Selected References
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- Allcock R. J., Peacock C. D., Price P. The inflammatory macrophage response to MCMV in mice with a retroviral immunodeficiency syndrome (MAIDS). J Leukoc Biol. 1996 Jul;60(1):44–50. doi: 10.1002/jlb.60.1.44. [DOI] [PubMed] [Google Scholar]
- Anderson K. P., Lie Y. S., Low M. A., Fennie E. H. Effects of tumor necrosis factor-alpha treatment on mortality in murine cytomegalovirus-infected mice. Antiviral Res. 1993 Aug;21(4):343–355. doi: 10.1016/0166-3542(93)90012-8. [DOI] [PubMed] [Google Scholar]
- Beutler B. A., Milsark I. W., Cerami A. Cachectin/tumor necrosis factor: production, distribution, and metabolic fate in vivo. J Immunol. 1985 Dec;135(6):3972–3977. [PubMed] [Google Scholar]
- Bursten S., Weeks R., West J., Le T., Wilson T., Porubek D., Bianco J. A., Singer J. W., Rice G. C. Potential role for phosphatidic acid in mediating the inflammatory responses to TNF alpha and IL-1 beta. Circ Shock. 1994 Sep;44(1):14–29. [PubMed] [Google Scholar]
- Dentener M. A., Greve J. W., Maessen J. G., Buurman W. A. Role of tumour necrosis factor in the enhanced sensitivity of mice to endotoxin after exposure to lead. Immunopharmacol Immunotoxicol. 1989;11(2-3):321–334. doi: 10.3109/08923978909005373. [DOI] [PubMed] [Google Scholar]
- Dinarello C. A. Interleukin-1. Ann N Y Acad Sci. 1988;546:122–132. doi: 10.1111/j.1749-6632.1988.tb21627.x. [DOI] [PubMed] [Google Scholar]
- Fanslow W. C., Sims J. E., Sassenfeld H., Morrissey P. J., Gillis S., Dower S. K., Widmer M. B. Regulation of alloreactivity in vivo by a soluble form of the interleukin-1 receptor. Science. 1990 May 11;248(4956):739–742. doi: 10.1126/science.2139736. [DOI] [PubMed] [Google Scholar]
- Fisher C. J., Jr, Agosti J. M., Opal S. M., Lowry S. F., Balk R. A., Sadoff J. C., Abraham E., Schein R. M., Benjamin E. Treatment of septic shock with the tumor necrosis factor receptor:Fc fusion protein. The Soluble TNF Receptor Sepsis Study Group. N Engl J Med. 1996 Jun 27;334(26):1697–1702. doi: 10.1056/NEJM199606273342603. [DOI] [PubMed] [Google Scholar]
- Griffiths P. D., Grundy J. E. Molecular biology and immunology of cytomegalovirus. Biochem J. 1987 Jan 15;241(2):313–324. doi: 10.1042/bj2410313. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Grundy J. E., Mackenzie J. S., Stanley N. F. Influence of H-2 and non-H-2 genes on resistance to murine cytomegalovirus infection. Infect Immun. 1981 Apr;32(1):277–286. doi: 10.1128/iai.32.1.277-286.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Haagmans B. L., Stals F. S., van der Meide P. H., Bruggeman C. A., Horzinek M. C., Schijns V. E. Tumor necrosis factor alpha promotes replication and pathogenicity of rat cytomegalovirus. J Virol. 1994 Apr;68(4):2297–2304. doi: 10.1128/jvi.68.4.2297-2304.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Haagmans B. L., van den Eertwegh A. J., Claassen E., Horzinek M. C., Schijns V. E. Tumour necrosis factor-alpha production during cytomegalovirus infection in immunosuppressed rats. J Gen Virol. 1994 Apr;75(Pt 4):779–787. doi: 10.1099/0022-1317-75-4-779. [DOI] [PubMed] [Google Scholar]
- Hopkins S. J., Humphreys M. Simple, sensitive and specific bioassay of interleukin-1. J Immunol Methods. 1989 Jun 21;120(2):271–276. doi: 10.1016/0022-1759(89)90252-4. [DOI] [PubMed] [Google Scholar]
- Klemola E., Käriäinen L., von Essen R., Haltia K., Koivuniemi A., von Bonsdorff C. H. Further studies on cytomegalovirus mononucleosis in previously healthy individuals. Acta Med Scand. 1967 Sep;182(3):311–322. doi: 10.1111/j.0954-6820.1967.tb11529.x. [DOI] [PubMed] [Google Scholar]
- Lane J. R., Neumann D. A., Lafond-Walker A., Herskowitz A., Rose N. R. Role of IL-1 and tumor necrosis factor in coxsackie virus-induced autoimmune myocarditis. J Immunol. 1993 Aug 1;151(3):1682–1690. [PubMed] [Google Scholar]
- Lathbury L. J., Allan J. E., Shellam G. R., Scalzo A. A. Effect of host genotype in determining the relative roles of natural killer cells and T cells in mediating protection against murine cytomegalovirus infection. J Gen Virol. 1996 Oct;77(Pt 10):2605–2613. doi: 10.1099/0022-1317-77-10-2605. [DOI] [PubMed] [Google Scholar]
- Lucin P., Jonjić S., Messerle M., Polić B., Hengel H., Koszinowski U. H. Late phase inhibition of murine cytomegalovirus replication by synergistic action of interferon-gamma and tumour necrosis factor. J Gen Virol. 1994 Jan;75(Pt 1):101–110. doi: 10.1099/0022-1317-75-1-101. [DOI] [PubMed] [Google Scholar]
- 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]
- Melnick J. L., Adam E., DeBakey M. E. Possible role of cytomegalovirus in atherogenesis. JAMA. 1990 Apr 25;263(16):2204–2207. [PubMed] [Google Scholar]
- Mestan J., Digel W., Mittnacht S., Hillen H., Blohm D., Möller A., Jacobsen H., Kirchner H. Antiviral effects of recombinant tumour necrosis factor in vitro. 1986 Oct 30-Nov 5Nature. 323(6091):816–819. doi: 10.1038/323816a0. [DOI] [PubMed] [Google Scholar]
- Mohler K. M., Torrance D. S., Smith C. A., Goodwin R. G., Stremler K. E., Fung V. P., Madani H., Widmer M. B. Soluble tumor necrosis factor (TNF) receptors are effective therapeutic agents in lethal endotoxemia and function simultaneously as both TNF carriers and TNF antagonists. J Immunol. 1993 Aug 1;151(3):1548–1561. [PubMed] [Google Scholar]
- Morris S. C., Madden K. B., Adamovicz J. J., Gause W. C., Hubbard B. R., Gately M. K., Finkelman F. D. Effects of IL-12 on in vivo cytokine gene expression and Ig isotype selection. J Immunol. 1994 Feb 1;152(3):1047–1056. [PubMed] [Google Scholar]
- Moses A. V., Garnett H. M. The effect of human cytomegalovirus on the production and biologic action of interleukin-1. J Infect Dis. 1990 Aug;162(2):381–388. doi: 10.1093/infdis/162.2.381. [DOI] [PubMed] [Google Scholar]
- Neumann D. A., Lane J. R., Allen G. S., Herskowitz A., Rose N. R. Viral myocarditis leading to cardiomyopathy: do cytokines contribute to pathogenesis? Clin Immunol Immunopathol. 1993 Aug;68(2):181–190. doi: 10.1006/clin.1993.1116. [DOI] [PubMed] [Google Scholar]
- Olver S. D., Price P., Shellam G. R. Cytomegalovirus hepatitis: characterization of the inflammatory infiltrate in resistant and susceptible mice. Clin Exp Immunol. 1994 Dec;98(3):375–381. doi: 10.1111/j.1365-2249.1994.tb05500.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Orange J. S., Biron C. A. An absolute and restricted requirement for IL-12 in natural killer cell IFN-gamma production and antiviral defense. Studies of natural killer and T cell responses in contrasting viral infections. J Immunol. 1996 Feb 1;156(3):1138–1142. [PubMed] [Google Scholar]
- Orange J. S., Wang B., Terhorst C., Biron C. A. Requirement for natural killer cell-produced interferon gamma in defense against murine cytomegalovirus infection and enhancement of this defense pathway by interleukin 12 administration. J Exp Med. 1995 Oct 1;182(4):1045–1056. doi: 10.1084/jem.182.4.1045. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pavić I., Polić B., Crnković I., Lucin P., Jonjić S., Koszinowski U. H. Participation of endogenous tumour necrosis factor alpha in host resistance to cytomegalovirus infection. J Gen Virol. 1993 Oct;74(Pt 10):2215–2223. doi: 10.1099/0022-1317-74-10-2215. [DOI] [PubMed] [Google Scholar]
- Price P., Eddy K. S., Papadimitriou J. M., Faulkner D. L., Shellam G. R. Genetic determination of cytomegalovirus-induced and age-related cardiopathy in inbred mice. Characterization of infiltrating cells. Am J Pathol. 1991 Jan;138(1):59–67. [PMC free article] [PubMed] [Google Scholar]
- Price P., Gibbons A. E., Shellam G. R. H-2 class I loci determine sensitivity to MCMV in macrophages and fibroblasts. Immunogenetics. 1990;32(1):20–26. doi: 10.1007/BF01787324. [DOI] [PubMed] [Google Scholar]
- Price P., Olver S. D., Gibbons A. E., Shellam G. R. B-cell activation following murine cytomegalovirus infection: implications for autoimmunity. Immunology. 1993 Jan;78(1):14–21. [PMC free article] [PubMed] [Google Scholar]
- Price P., Olver S. D., Gibbons A. E., Teo H. K., Shellam G. R. Characterization of thymic involution induced by murine cytomegalovirus infection. Immunol Cell Biol. 1993 Jun;71(Pt 3):155–165. doi: 10.1038/icb.1993.18. [DOI] [PubMed] [Google Scholar]
- Price P., Olver S. D., Silich M., Nador T. Z., Yerkovich S., Wilson S. G. Adrenalitis and the adrenocortical response of resistant and susceptible mice to acute murine cytomegalovirus infection. Eur J Clin Invest. 1996 Sep;26(9):811–819. doi: 10.1046/j.1365-2362.1996.2210562.x. [DOI] [PubMed] [Google Scholar]
- Price P., Winter J. G., Shellam G. R. Genetically determined resistance to murine cytomegalovirus: a role for lymphocytostatic macrophages. J Gen Virol. 1987 Dec;68(Pt 12):2997–3008. doi: 10.1099/0022-1317-68-12-2997. [DOI] [PubMed] [Google Scholar]
- Price P., Winter J. G., Shellam G. R. The inflammatory macrophage response to murine cytomegalovirus in genetically susceptible mice. Arch Virol. 1989;106(1-2):35–50. doi: 10.1007/BF01311036. [DOI] [PubMed] [Google Scholar]
- Rice G. C., Brown P. A., Nelson R. J., Bianco J. A., Singer J. W., Bursten S. Protection from endotoxic shock in mice by pharmacologic inhibition of phosphatidic acid. Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):3857–3861. doi: 10.1073/pnas.91.9.3857. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Scalzo A. A., Fitzgerald N. A., Simmons A., La Vista A. B., Shellam G. R. Cmv-1, a genetic locus that controls murine cytomegalovirus replication in the spleen. J Exp Med. 1990 May 1;171(5):1469–1483. doi: 10.1084/jem.171.5.1469. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Scalzo A. A., Fitzgerald N. A., Wallace C. R., Gibbons A. E., Smart Y. C., Burton R. C., Shellam G. R. The effect of the Cmv-1 resistance gene, which is linked to the natural killer cell gene complex, is mediated by natural killer cells. J Immunol. 1992 Jul 15;149(2):581–589. [PubMed] [Google Scholar]
- Shanley J. D., Goff E., Debs R. J., Forman S. J. The role of tumor necrosis factor-alpha in acute murine cytomegalovirus infection in BALB/c mice. J Infect Dis. 1994 May;169(5):1088–1091. doi: 10.1093/infdis/169.5.1088. [DOI] [PubMed] [Google Scholar]
- Shusterman N. H., Frauenhoffer C., Kinsey M. D. Fatal massive hepatic necrosis in cytomegalovirus mononucleosis. Ann Intern Med. 1978 Jun;88(6):810–812. doi: 10.7326/0003-4819-88-6-810. [DOI] [PubMed] [Google Scholar]
- Smith P. D., Saini S. S., Raffeld M., Manischewitz J. F., Wahl S. M. Cytomegalovirus induction of tumor necrosis factor-alpha by human monocytes and mucosal macrophages. J Clin Invest. 1992 Nov;90(5):1642–1648. doi: 10.1172/JCI116035. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Snover D. C., Horwitz C. A. Liver disease in cytomegalovirus mononucleosis: a light microscopical and immunoperoxidase study of six cases. Hepatology. 1984 May-Jun;4(3):408–412. doi: 10.1002/hep.1840040309. [DOI] [PubMed] [Google Scholar]
- Stevens T. L., Bossie A., Sanders V. M., Fernandez-Botran R., Coffman R. L., Mosmann T. R., Vitetta E. S. Regulation of antibody isotype secretion by subsets of antigen-specific helper T cells. Nature. 1988 Jul 21;334(6179):255–258. doi: 10.1038/334255a0. [DOI] [PubMed] [Google Scholar]
- Tilg H., Vogel W., Herold M., Aulitzky W. E., Huber C. Cachexia and tumour necrosis factor-alpha in cytomegalovirus infection. J Clin Pathol. 1991 Jun;44(6):519–520. doi: 10.1136/jcp.44.6.519. [DOI] [PMC free article] [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]
- Watanabe Y., Morita M., Ikematsu N., Akaike T. Tumor necrosis factor alpha and interleukin-1 beta but not interferon gamma induce vascular cell adhesion molecule-1 expression on primary cultured murine hepatocytes. Biochem Biophys Res Commun. 1995 Apr 6;209(1):335–342. doi: 10.1006/bbrc.1995.1508. [DOI] [PubMed] [Google Scholar]
- Wong G. H., Goeddel D. V. Tumour necrosis factors alpha and beta inhibit virus replication and synergize with interferons. 1986 Oct 30-Nov 5Nature. 323(6091):819–822. doi: 10.1038/323819a0. [DOI] [PubMed] [Google Scholar]
- Zuckerman S. H., Shellhaas J., Butler L. D. Differential regulation of lipopolysaccharide-induced interleukin 1 and tumor necrosis factor synthesis: effects of endogenous and exogenous glucocorticoids and the role of the pituitary-adrenal axis. Eur J Immunol. 1989 Feb;19(2):301–305. doi: 10.1002/eji.1830190213. [DOI] [PubMed] [Google Scholar]
- van Bruggen I., Price P., Robertson T. A., Papadimitriou J. M. Morphological and functional changes during cytomegalovirus replication in murine macrophages. J Leukoc Biol. 1989 Dec;46(6):508–520. doi: 10.1002/jlb.46.6.508. [DOI] [PubMed] [Google Scholar]