1887

Abstract

Interleukin (IL)-12 is an important proinflammatory and immunoregulatory cytokine expressed primarily by macrophages. Although IL-12 appears to be essential for clearance of many bacterial and parasitic infections, only little is known about the production and regulation of this cytokine during viral infections. In this study we have shown that infection of mouse macrophages with herpes simplex virus type 2 (HSV-2) induces secretion of the p40 subunit of IL-12, and this induction was synergistically enhanced by interferon (IFN)-γ. The production of IL-12 p40 was accompanied by production of bioactive IL-12 p70, since HSV-2-induced IFN-γ secretion was blocked by neutralizing antibodies against IL-12. The IL-12-inducing effect of HSV-2 was abrogated when virus infectivity was destroyed by heat or UV irradiation, indicating that a functional viral genome is required and that interaction of viral glycoproteins with cellular receptors is not sufficient. Production of IL-12 p40 was transcriptionally regulated and required protein synthesis. Although IFN-α, IL-1β and tumour necrosis factor-α marginally influenced IL-12 production, they did not seem to constitute the endogenous factor(s) responsible for the effect of the virus infection. HSV-2 infection induced nuclear-binding activity to the κB halfsite of the IL-12 p40 promoter, and inhibitors of nuclear factor (NF)-κB activation significantly reduced IL-12 p40 production in infected cells. Collectively our data show that HSV-2 infection of murine macrophages induces production of IL-12 through a mechanism requiring intermediary synthesis of viral or host proteins and involving activation of NF-κB.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/0022-1317-81-12-3011
2000-12-01
2019-12-14
Loading full text...

Full text loading...

/deliver/fulltext/jgv/81/12/0813011a.html?itemId=/content/journal/jgv/10.1099/0022-1317-81-12-3011&mimeType=html&fmt=ahah

References

  1. Ankel, H., Westra, D. F., Welling-Wester, S. & Lebon, P. ( 1998; ). Induction of interferon-α by glycoprotein D of herpes simplex virus: a possible role of chemokine receptors. Virology 251, 317-326.[CrossRef]
    [Google Scholar]
  2. Aste-Amezaga, M., Ma, X., Sartori, A. & Trinchieri, G. ( 1998; ). Molecular mechanisms of the induction of IL-12 and its inhibition by IL-10. Journal of Immunology 160, 5936-5944.
    [Google Scholar]
  3. Babik, J. M., Adams, E., Tone, Y., Fairchild, P. J., Tone, M. & Waldmann, H. ( 1999; ). Expression of murine IL-12 is regulated by translational control of the p35 subunit. Journal of Immunology 162, 4069-4078.
    [Google Scholar]
  4. Baskin, H., Ellermann-Eriksen, S., Lovmand, J. & Mogensen, S. C. ( 1997; ). Herpes simplex virus type 2 synergizes with interferon-α in the induction of nitric oxide production in mouse macrophages through autocrine secretion of tumour necrosis factor-α. Journal of General Virology 78, 195-203.
    [Google Scholar]
  5. Biron, C. A. ( 1998; ). Role of early cytokines, including α and β interferons (IFN-α/β), in innate and adaptive immune responses to viral infections. Seminars in Immunology 10, 383-390.[CrossRef]
    [Google Scholar]
  6. Biron, C. A., Nguyen, K. B., Pien, G. C., Cousens, L. P. & Salazar-Mather, T. P. ( 1999; ). Natural killer cells in antiviral defense: function and regulation by innate cytokines. Annual Review of Immunology 17, 189-220.[CrossRef]
    [Google Scholar]
  7. Cantin, E., Tanamachi, B., Openshaw, H., Mann, J. & Clarke, K. ( 1999; ). Gamma interferon (IFN-γ) receptor null-mutant mice are more susceptible to herpes simplex virus type 1 infection than IFN-γ ligand null-mutant mice. Journal of Virology 73, 5196-5200.
    [Google Scholar]
  8. Carr, J. A., Rogerson, J., Mulqueen, M. J., Roberts, N. A. & Booth, R. F. ( 1997; ). Interleukin-12 exhibits potent antiviral activity in experimental herpesvirus infections. Journal of Virology 71, 7799-7803.
    [Google Scholar]
  9. Carr, J. A., Rogerson, J., Mulqueen, M. J., Roberts, N. A. & Nash, A. A. ( 1999; ). The role of endogenous interleukin-12 in resistance to murine cytomegalovirus (MCMV) infection and a novel action for endogenous IL-12 p40. Journal of Interferon and Cytokine Research 19, 1145-1152.[CrossRef]
    [Google Scholar]
  10. Cousens, L. P., Orange, J. S., Su, H. C. & Biron, C. A. ( 1997; ). Interferon-α/β inhibition of interleukin 12 and interferon-γ production in vitro and endogenously during viral infection. Proceedings of the National Academy of Sciences, USA 94, 634-639.[CrossRef]
    [Google Scholar]
  11. Cousens, L. P., Peterson, R., Hsu, S., Dorner, A., Altman, J. D., Ahmed, R. & Biron, C. A. ( 1999; ). Two roads diverged: interferon α/β- and interleukin-12-mediated pathways in promoting T cell interferon γ responses during viral infection. Journal of Experimental Medicine 189, 1315-1328.[CrossRef]
    [Google Scholar]
  12. Coutelier, J. P., Van Broeck, J. & Wolf, S. F. ( 1995; ). Interleukin-12 gene expression after viral infection in the mouse. Journal of Virology 69, 1955-1958.
    [Google Scholar]
  13. D’Ambrosio, D., Cippitelli, M., Cocciolo, M. G., Mazzeo, D., Di Lucia, P., Lang, R., Sinigaglia, F. & Panina-Bordignon, P. ( 1998; ). Inhibition of IL-12 production by 1,25-dihydroxyvitamin D3. Involvement of NF-κB downregulation in transcriptional repression of the p40 gene. Journal of Clinical Investigation 101, 252-262.[CrossRef]
    [Google Scholar]
  14. D’Andrea, A., Rengaraju, M., Valiante, N. M., Chehimi, J., Kubin, M., Aste, M., Chan, S. H., Kobayashi, M., Young, D. & Nickbarg, E. ( 1992; ). Production of natural killer cell stimulatory factor (interleukin 12) by peripheral blood mononuclear cells. Journal of Experimental Medicine 176, 1387-1398.[CrossRef]
    [Google Scholar]
  15. Ellermann-Eriksen, S. ( 1993; ). Autocrine secretion of interferon-α/β and tumour necrosis factor-α synergistically activates mouse macrophages after infection with herpes simplex virus type 2. Journal of General Virology 74, 2191-2199.[CrossRef]
    [Google Scholar]
  16. Ellermann-Eriksen, S., Liberto, M. C., Iannello, D. & Mogensen, S. C. ( 1986; ). X-linkage of the early in vitro α/β interferon response of mouse peritoneal macrophages to herpes simplex virus type 2. Journal of General Virology 67, 1025-1033.[CrossRef]
    [Google Scholar]
  17. Flesch, I. E., Hess, J. H., Huang, S., Aguet, M., Rothe, J., Bluethmann, H. & Kaufmann, S. H. ( 1995; ). Early interleukin 12 production by macrophages in response to mycobacterial infection depends on interferon γ and tumor necrosis factor α. Journal of Experimental Medicine 181, 1615-1621.[CrossRef]
    [Google Scholar]
  18. Gazzinelli, R. T., Wysocka, M., Hayashi, S., Denkers, E. Y., Hieny, S., Caspar, P., Trinchieri, G. & Sher, A. ( 1994; ). Parasite-induced IL-12 stimulates early IFN-γ synthesis and resistance during acute infection with Toxoplasma gondii. Journal of Immunology 153, 2533-2543.
    [Google Scholar]
  19. Gri, G., Savio, D., Trinchieri, G. & Ma, X. ( 1998; ). Synergistic regulation of the human interleukin-12 p40 promoter by NF-κB and Ets transcription factors in Epstein-Barr virus-transformed B cells and macrophages. Journal of Biological Chemistry 273, 6431-6438.[CrossRef]
    [Google Scholar]
  20. Hayes, M. P., Wang, J. & Norcross, M. A. ( 1995; ). Regulation of interleukin-12 expression in human monocytes: selective priming by interferon-γ of lipopolysaccharide-inducible p35 and p40 genes. Blood 86, 646-650.
    [Google Scholar]
  21. Heinzel, F. P., Schoenhaut, D. S., Rerko, R. M., Rosser, L. E. & Gately, M. K. ( 1993; ). Recombinant interleukin 12 cures mice infected with Leishmania major. Journal of Experimental Medicine 177, 1505-1509.[CrossRef]
    [Google Scholar]
  22. Heise, M. T. & Virgin, H. W. ( 1995; ). The T-cell-independent role of γ interferon and tumor necrosis factor-α in macrophage activation during murine cytomegalovirus and herpes simplex virus infections. Journal of Virology 69, 904-909.
    [Google Scholar]
  23. Heufler, C., Koch, F., Stanzl, U., Topar, G., Wysocka, M., Trinchieri, G., Enk, A., Steinman, R. M., Romani, N. & Schuler, G. ( 1996; ). Interleukin-12 is produced by dendritic cells and mediates T helper 1 development as well as interferon-α production by T helper 1 cells. European Journal of Immunology 26, 659-668.[CrossRef]
    [Google Scholar]
  24. Hsieh, C. S., Macatonia, S. E., Tripp, C. S., Wolf, S. F., O’Garra, A. & Murphy, K. M. ( 1993; ). Development of TH1 CD4+T cells through IL-12 produced by Listeria-induced macrophages. Science 260, 547-549.[CrossRef]
    [Google Scholar]
  25. Kanangat, S., Thomas, J., Gangappa, S., Babu, J. S. & Rouse, B. T. ( 1996; ). Herpes simplex virus type 1-mediated up-regulation of IL-12 (p40) mRNA expression. Implications in immunopathogenesis and protection. Journal of Immunology 156, 1110-1116.
    [Google Scholar]
  26. Kang, B. Y., Chung, S. W., Im, S. Y., Hwang, S. Y. & Kim, T. S. ( 1999; ). Chloromethyl ketones inhibit interleukin-12 production in mouse macrophages stimulated with lipopolysaccharide. Immunology Letters 70, 135-138.[CrossRef]
    [Google Scholar]
  27. Kobayashi, M., Fitz, L., Ryan, M., Hewick, R. M., Clark, S. C., Chan, S., Loudon, R., Sherman, F., Perussia, B. & Trinchieri, G. ( 1989; ). Identification and purification of natural killer cell stimulatory factor (NKSF), a cytokine with multiple biologic effects on human lymphocytes. Journal of Experimental Medicine 170, 827-845.[CrossRef]
    [Google Scholar]
  28. Ma, X., Aste-Amezaga, M. & Trinchieri, G. ( 1996a; ). Regulation of interleukin-12 production. Annals of the New York Academy of Sciences 795, 13-25.[CrossRef]
    [Google Scholar]
  29. Ma, X., Chow, J. M., Gri, G., Carra, G., Gerosa, F., Wolf, S. F., Dzialo, R. & Trinchieri, G. ( 1996b; ). The interleukin 12 p40 gene promoter is primed by interferon γ in monocytic cells. Journal of Experimental Medicine 183, 147-157.[CrossRef]
    [Google Scholar]
  30. Macatonia, S. E., Hosken, N. A., Litton, M., Vieira, P., Hsieh, C. S., Culpepper, J. A., Wysocka, M., Trinchieri, G., Murphy, K. M. & O’Garra, A. ( 1995; ). Dendritic cells produce IL-12 and direct the development of Th1 cells from naive CD4+ T cells. Journal of Immunology 154, 5071-5079.
    [Google Scholar]
  31. Mazzeo, D., Panina-Bordignon, P., Recalde, H., Sinigaglia, F. & D’Ambrosio, D. ( 1998; ). Decreased IL-12 production and Th1 cell development by acetyl salicylic acid-mediated inhibition of NF-κB. European Journal of Immunology 28, 3205-3213.[CrossRef]
    [Google Scholar]
  32. Mogensen, S. C. ( 1984; ). Host defences in mice against infections with herpes simplex virus. Microbiological Sciences 1, 127-130.
    [Google Scholar]
  33. Mogensen, S. C. & Virelizier, J. L. ( 1987; ). The interferon-macrophage alliance. Interferon 8, 55-84.
    [Google Scholar]
  34. Monteiro, J. M., Harvey, C. & Trinchieri, G. ( 1998; ). Role of interleukin-12 in primary influenza virus infection. Journal of Virology 72, 4825-4831.
    [Google Scholar]
  35. Murphy, T. L., Cleveland, M. G., Kulesza, P., Magram, J. & Murphy, K. M. ( 1995; ). Regulation of interleukin 12 p40 expression through an NF-κB half-site. Molecular and Cellular Biology 15, 5258-5267.
    [Google Scholar]
  36. Na, S. Y., Kang, B. Y., Chung, S. W., Han, S. J., Ma, X., Trinchieri, G., Im, S. Y., Lee, J. W. & Kim, T. S. ( 1999; ). Retinoids inhibit interleukin-12 production in macrophages through physical associations of retinoid X receptor and NF-κB. Journal of Biological Chemistry 274, 7674-7680.[CrossRef]
    [Google Scholar]
  37. Orange, J. S. & Biron, C. A. ( 1996a; ). An absolute and restricted requirement for IL-12 in natural killer cell IFN-γ production and antiviral defense. Studies of natural killer and T cell responses in contrasting viral infections. Journal of Immunology 156, 1138-1142.
    [Google Scholar]
  38. Orange, J. S. & Biron, C. A. ( 1996b; ). Characterization of early IL-12, IFN-α/β, and TNF effects on antiviral state and NK cell responses during murine cytomegalovirus infection. Journal of Immunology 156, 4746-4756.
    [Google Scholar]
  39. Parr, M. B. & Parr, E. L. ( 1999; ). The role of γ interferon in immune resistance to vaginal infection by herpes simplex virus type 2 in mice. Virology 258, 282-294.[CrossRef]
    [Google Scholar]
  40. Patel, A., Hanson, J., McLean, T. I., Olgiate, J., Hilton, M., Miller, W. E. & Bachenheimer, S. L. ( 1998; ). Herpes simplex type 1 induction of persistent NF-κB nuclear translocation increases the efficiency of virus replication. Virology 247, 212-222.[CrossRef]
    [Google Scholar]
  41. Plevy, S. E., Gemberling, J. H., Hsu, S., Dorner, A. J. & Smale, S. T. ( 1997; ). Multiple control elements mediate activation of the murine and human interleukin 12 p40 promoters: evidence of functional synergy between C/EBP and Rel proteins. Molecular and Cellular Biology 17, 4572-4588.
    [Google Scholar]
  42. Sareneva, T., Matikainen, S., Kurimoto, M. & Julkunen, I. ( 1998; ). Influenza A virus-induced IFN-α/β and IL-18 synergistically enhance IFN-γ gene expression in human T cells. Journal of Immunology 160, 6032-6038.
    [Google Scholar]
  43. Schijns, V. E., Wierda, C. M., van Hoeij, M. & Horzinek, M. C. ( 1996; ). Exacerbated viral hepatitis in IFN-γ receptor-deficient mice is not suppressed by IL-12. Journal of Immunology 157, 815-821.
    [Google Scholar]
  44. Schijns, V. E., Haagmans, B. L., Wierda, C. M., Kruithof, B., Heijnen, I. A., Alber, G. & Horzinek, M. C. ( 1998; ). Mice lacking IL-12 develop polarized Th1 cells during viral infection. Journal of Immunology 160, 3958-3964.
    [Google Scholar]
  45. Skeen, M. J., Miller, M. A., Shinnick, T. M. & Ziegler, H. K. ( 1996; ). Regulation of murine macrophage IL-12 production. Activation of macrophages in vivo, restimulation in vitro, and modulation by other cytokines. Journal of Immunology 156, 1196-1206.
    [Google Scholar]
  46. Snijders, A., Hilkens, C. M., van der Pouw Kraan, T. C., Engel, M., Aarden, L. A. & Kapsenberg, M. L. ( 1996; ). Regulation of bioactive IL-12 production in lipopolysaccharide-stimulated human monocytes is determined by the expression of the p35 subunit. Journal of Immunology 156, 1207-1212.
    [Google Scholar]
  47. 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. ( 1990; ). Purification to homogeneity and partial characterization of cytotoxic lymphocyte maturation factor from human B-lymphoblastoid cells. Proceedings of the National Academy of Sciences, USA 87, 6808-6812.[CrossRef]
    [Google Scholar]
  48. Trinchieri, G. ( 1995; ). Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity. Annual Review of Immunology 13, 251-276.[CrossRef]
    [Google Scholar]
  49. Tripp, C. S., Gately, M. K., Hakimi, J., Ling, P. & Unanue, E. R. ( 1994; ). Neutralization of IL-12 decreases resistance to Listeria in SCID and C.B-17 mice. Reversal by IFN-γ. Journal of Immunology 152, 1883-1887.
    [Google Scholar]
  50. Yoshimoto, T., Nagase, H., Ishida, T., Inoue, J. & Nariuchi, H. ( 1997; ). Induction of interleukin-12 p40 transcript by CD40 ligation via activation of nuclear factor-κB. European Journal of Immunology 27, 3461-3470.[CrossRef]
    [Google Scholar]
  51. Yu, Z., Manickan, E. & Rouse, B. T. ( 1996; ). Role of interferon-γ in immunity to herpes simplex virus. Journal of Leukocyte Biology 60, 528-532.
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/0022-1317-81-12-3011
Loading
/content/journal/jgv/10.1099/0022-1317-81-12-3011
Loading

Data & Media loading...

Most Cited This Month

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