1887

Abstract

Interleukin-10 (IL-10) plays a critical role in Epstein–Barr virus (EBV) biology. Indeed, the EBV genome contains a gene (BCRF1) with homology to the human IL-10 (hIL-10) gene. In addition to viral IL-10, which is secreted late in the productive cycle, hIL-10 production is also induced in B cells infected by EBV. The EBV protein LMP-1 and the viral small non-polyadenylated RNAs (EBERs) expressed during latency are involved in hIL-10 induction. In this study, we show that in B cells the viral transcription factor EB1, which is the main inducer of the EBV productive cycle, also activates transcription of the hIL-10 gene and secretion of the hIL-10 protein. Accordingly, EB1 bound directly to specific DNA sequences in the hIL-10 minimal promoter. Moreover, specific disruption of EB1 binding to some of these sites impaired EB1-mediated activation of transcription at the hIL-10 promoter in a transient expression assay. Therefore, an increase in IL-10 production occurs during latency and early and late during the productive cycle. This production of IL-10 might favour the survival of EBV-infected cells and/or create a microenvironment required for efficient infection of B lymphocytes by EBV virions.

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2003-04-01
2019-09-22
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References

  1. Adamson, A. L. & Kenney, S. ( 2001; ). Epstein–Barr virus immediate-early protein BZLF1 is SUMO-1 modified and disrupts promyelocytic leukemia bodies. J Virol 75, 2388–2399.[CrossRef]
    [Google Scholar]
  2. Badou, A., Bennasser, Y., Moreau, M., Leclerc, C., Benkirane, M. & Bahraoui, E. ( 2000; ). Tat protein of human immunodeficiency virus type 1 induces interleukin-10 in human peripheral blood monocytes: implication of protein kinase C-dependent pathway. J Virol 74, 10551–10562.[CrossRef]
    [Google Scholar]
  3. Bejarano, M. T. & Masucci, M. G. ( 1998; ). Interleukin-10 abrogates the inhibition of Epstein–Barr virus-induced B-cell transformation by memory T-cell responses. Blood 92, 4256–4262.
    [Google Scholar]
  4. Birkeland, S. A., Bendtzen, K., Moller, B., Hamilton-Dutoit, S. & Andersen, H. K. ( 1999; ). Interleukin-10 and posttransplant lymphoproliferative disorder after kidney transplantation. Transplantation 67, 876–881.[CrossRef]
    [Google Scholar]
  5. Cayrol, C. & Flemington, E. K. ( 1995; ). Identification of cellular target genes of the Epstein–Barr virus transactivator Zta: activation of transforming growth factor βigh3 (TGF-βigh3) and TGF-β1. J Virol 69, 4206–4212.
    [Google Scholar]
  6. Chevallier-Greco, A., Manet, E., Chavrier, P., Mosnier, C., Daillie, J. & Sergeant, A. ( 1986; ). Both Epstein–Barr virus (EBV)-encoded trans-acting factors, EB1 and EB2, are required to activate transcription from an EBV early promoter. EMBO J 5, 3243–3249.
    [Google Scholar]
  7. Cortes, J. & Kurzrock, R. ( 1997; ). Interleukin-10 in non-Hodgkin's lymphoma. Leuk Lymphoma 26, 251–259.
    [Google Scholar]
  8. Countryman, J., Jenson, H., Seibl, R., Wolf, H. & Miller, G. ( 1987; ). Polymorphic proteins encoded within BZLF1 of defective and standard Epstein–Barr viruses disrupt latency. J Virol 61, 3672–3679.
    [Google Scholar]
  9. de Waal Malefyt, R., Haanen, J., Spits, H., Roncarolo, M. G., te Velde, A., Figdor, C., Johnson, K., Kastelein, R., Yssel, H. & de Vries, J. E. ( 1991; ). Interleukin 10 (IL-10) and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of monocytes via downregulation of class II major histocompatibility complex expression. J Exp Med 174, 915–924.[CrossRef]
    [Google Scholar]
  10. de Waal Malefyt, R., Yssel, H. & de Vries, J. E. ( 1993; ). Direct effects of IL-10 on subsets of human CD4+ T cell clones and resting T cells. Specific inhibition of IL-2 production and proliferation. J Immunol 150, 4754–4765.
    [Google Scholar]
  11. Erickson, K. D. & Martin, J. M. ( 2000; ). The late lytic LMP-1 protein of Epstein–Barr virus can negatively regulate LMP-1 signaling. J Virol 74, 1057–1060.[CrossRef]
    [Google Scholar]
  12. Eskdale, J., Kube, D., Tesch, H. & Gallagher, G. ( 1997; ). Mapping of the human IL10 gene and further characterization of the 5′ flanking sequence. Immunogenetics 46, 120–128.[CrossRef]
    [Google Scholar]
  13. Farrell, P. J., Rowe, D. T., Rooney, C. M. & Kouzarides, T. ( 1989; ). Epstein–Barr virus BZLF1 trans-activator specifically binds to a consensus AP-1 site and is related to c-fos. EMBO J 8, 127–132.
    [Google Scholar]
  14. Flemington, E. & Speck, S. H. ( 1990; ). Epstein–Barr virus BZLF1 trans activator induces the promoter of a cellular cognate gene, c-fos. J Virol 64, 4549–4552.
    [Google Scholar]
  15. Giot, J. F., Mikaelian, I., Buisson, M., Manet, E., Joab, I., Nicolas, J. C. & Sergeant, A. ( 1991; ). Transcriptional interference between the EBV transcription factors EB1 and R: both DNA-binding and activation domains of EB1 are required. Nucleic Acids Res 19, 1251–1258.[CrossRef]
    [Google Scholar]
  16. Herbst, H., Foss, H. D., Samol, J., Araujo, I., Klotzbach, H., Krause, H., Agathanggelou, A., Niedobitek, G. & Stein, H. ( 1996; ). Frequent expression of interleukin-10 by Epstein–Barr virus-harboring tumor cells of Hodgkin's disease. Blood 87, 2918–2929.
    [Google Scholar]
  17. Hudson, G. S., Farrell, P. J. & Barrell, B. G. ( 1985; ). Two related but differentially expressed potential membrane proteins encoded by the EcoRI Dhet region of Epstein–Barr virus B95-8. J Virol 53, 528–535.
    [Google Scholar]
  18. Keating, S., Prince, S., Jones, M. & Rowe, M. ( 2002; ). The lytic cycle of Epstein–Barr virus is associated with decreased expression of cell surface major histocompatibility complex class I and class II molecules. J Virol 76, 8179–8188.[CrossRef]
    [Google Scholar]
  19. Kieff, E. & Rickinson, A. B. ( 2001; ). Epstein–Barr virus and its replication. In Fields Virology, 4th edn, pp. 2511–2573. Edited by D. M. Knipe & P. M. Howley. Philadelphia, Lippincott Williams & Wilkins.
  20. Kitagawa, N., Goto, M., Kurozumi, K., Maruo, S., Fukayama, M., Naoe, T., Yasukawa, M., Hino, K., Suzuki, T., Todo, S. & Takada, K. ( 2000; ). Epstein–Barr virus-encoded poly(A) (−)RNA supports Burkitt's lymphoma growth through interleukin-10 induction. EMBO J 19, 6742–6750.[CrossRef]
    [Google Scholar]
  21. Klein, S. C., Kube, D., Abts, H., Diehl, V. & Tesch, H. ( 1996; ). Promotion of IL8, IL10, TNF alpha and TNF beta production by EBV infection. Leuk Res 20, 633–636.[CrossRef]
    [Google Scholar]
  22. Kube, D., Platzer, C., von Knethen, A., Straub, H., Bohlen, H., Hafner, M. & Tesch, H. ( 1995; ). Isolation of the human interleukin 10 promoter. Characterization of the promoter activity in Burkitt's lymphoma cell lines. Cytokine 7, 1–7.[CrossRef]
    [Google Scholar]
  23. Lieberman, P. M., Hardwick, J. M., Sample, J., Hayward, G. S. & Hayward, S. D. ( 1990; ). The zta transactivator involved in induction of lytic cycle gene expression in Epstein–Barr virus-infected lymphocytes binds to both AP-1 and ZRE sites in target promoter and enhancer regions. J Virol 64, 1143–1155.
    [Google Scholar]
  24. Lu, J., Chen, S. Y., Chua, H. H., Liu, Y. S., Huang, Y. T., Chang, Y., Chen, J. Y., Sheen, T. S. & Tsai, C. H. ( 2000; ). Upregulation of tyrosine kinase TKT by the Epstein–Barr virus transactivator Zta. J Virol 74, 7391–7399.[CrossRef]
    [Google Scholar]
  25. Manet, E., Gruffat, H., Trescol-Biemont, M. C., Moreno, N., Chambard, P., Giot, J. F. & Sergeant, A. ( 1989; ). Epstein–Barr virus bicistronic mRNAs generated by facultative splicing code for two transcriptional trans-activators. EMBO J 8, 1819–1826.
    [Google Scholar]
  26. Mikaelian, I., Drouet, E., Marechal, V., Denoyel, G., Nicolas, J. C. & Sergeant, A. ( 1993; ). The DNA-binding domain of two bZIP transcription factors, the Epstein–Barr virus switch gene product EB1 and Jun, is a bipartite nuclear targeting sequence. J Virol 67, 734–742.
    [Google Scholar]
  27. Miyazaki, I., Cheung, R. K. & Dosch, H. M. ( 1993; ). Viral interleukin 10 is critical for the induction of B cell growth transformation by Epstein–Barr virus. J Exp Med 178, 439–447.[CrossRef]
    [Google Scholar]
  28. Moore, K. W., Vieira, P., Fiorentino, D. F., Trounstine, M. L., Khan, T. A. & Mosmann, T. R. ( 1990; ). Homology of cytokine synthesis inhibitory factor (IL-10) to the Epstein–Barr virus gene BCRFI. Science 248, 1230–1234.[CrossRef]
    [Google Scholar]
  29. Moore, K. W., de Waal Malefyt, R., Coffman, R. L. & O'Garra, A. ( 2001; ). Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 19, 683–765.[CrossRef]
    [Google Scholar]
  30. Morrison, T. E., Mauser, A., Wong, A., Ting, J. P. & Kenney, S. C. ( 2001; ). Inhibition of IFN-γ signaling by an Epstein–Barr virus immediate-early protein. Immunity 15, 787–799.[CrossRef]
    [Google Scholar]
  31. Nakagomi, H., Dolcetti, R., Bejarano, M. T., Pisa, P., Kiessling, R. & Masucci, M. G. ( 1994; ). The Epstein–Barr virus latent membrane protein-1 (LMP1) induces interleukin-10 production in Burkitt lymphoma lines. Int J Cancer 57, 240–244.[CrossRef]
    [Google Scholar]
  32. Ohshima, K., Suzumiya, J., Akamatu, M., Takeshita, M. & Kikuchi, M. ( 1995; ). Human and viral interleukin-10 in Hodgkin's disease, and its influence on CD4+ and CD8+ T lymphocytes. Int J Cancer 62, 5–10.[CrossRef]
    [Google Scholar]
  33. Payvandi, F., Amrute, S. & Fitzgerald-Bocarsly, P. ( 1998; ). Exogenous and endogenous IL-10 regulate IFN-α production by peripheral blood mononuclear cells in response to viral stimulation. J Immunol 160, 5861–5868.
    [Google Scholar]
  34. Rickinson, A. B. & Kieff, E. ( 1996; ). Epstein-Barr virus. In Fields Virology, 3rd edn, pp. 2397–446. Edited by B. N. Fields, D. M. Knipe & P. M. Howley. Philadelphia: Lippincott–Raven.
  35. Rickinson, A. B. & Moss, D. J. ( 1997; ). Human cytotoxic T lymphocyte responses to Epstein–Barr virus infection. Annu Rev Immunol 15, 405–431.[CrossRef]
    [Google Scholar]
  36. Rousset, F., Garcia, E., Defrance, T., Peronne, C., Vezzio, N., Hsu, D. H., Kastelein, R., Moore, K. W. & Banchereau, J. ( 1992; ). Interleukin 10 is a potent growth and differentiation factor for activated human B lymphocytes. Proc Natl Acad Sci U S A 89, 1890–1893.[CrossRef]
    [Google Scholar]
  37. Sairenji, T., Ohnishi, E., Inouye, S. & Kurata, T. ( 1998; ). Induction of interleukin-10 on activation of Epstein–Barr virus in EBV-infected B-cell lines. Viral Immunol 11, 221–231.[CrossRef]
    [Google Scholar]
  38. Schepers, A., Pich, D. & Hammerschmidt, W. ( 1993; ). A transcription factor with homology to the AP-1 family links RNA transcription and DNA replication in the lytic cycle of Epstein–Barr virus. EMBO J 12, 3921–3929.
    [Google Scholar]
  39. Shaw, P. E., Bohmann, D. & Sergeant, A. ( 1985; ). The SV40 enhancer influences viral late transcription in vitro and in vivo but not on replicating templates. EMBO J 4, 3247–3252.
    [Google Scholar]
  40. Speck, S. H., Chatila, T. & Flemington, E. ( 1997; ). Reactivation of Epstein–Barr virus: regulation and function of the BZLF1 gene. Trends Microbiol 5, 399–405.[CrossRef]
    [Google Scholar]
  41. Swaminathan, S., Hesselton, R., Sullivan, J. & Kieff, E. ( 1993; ). Epstein–Barr virus recombinants with specifically mutated BCRF1 genes. J Virol 67, 7406–7413.
    [Google Scholar]
  42. Thorley-Lawson, D. A. ( 2001; ). Epstein–Barr virus: exploiting the immune system. Nature Rev Immunol 1, 75–82.[CrossRef]
    [Google Scholar]
  43. Urier, G., Buisson, M., Chambard, P. & Sergeant, A. ( 1989; ). The Epstein–Barr virus early protein EB1 activates transcription from different responsive elements including AP-1 binding sites. EMBO J 8, 1447–1453.
    [Google Scholar]
  44. Vockerodt, M., Haier, B., Buttgereit, P., Tesch, H. & Kube, D. ( 2001; ). The Epstein–Barr virus latent membrane protein 1 induces interleukin-10 in Burkitt's lymphoma cells but not in Hodgkin's cells involving the p38/SAPK2 pathway. Virology 280, 183–198.[CrossRef]
    [Google Scholar]
  45. Yao, M., Ohshima, K., Suzumiya, J., Kume, T., Shiroshita, T. & Kikuchi, M. ( 1997; ). Interleukin-10 expression and cytotoxic-T-cell response in Epstein–Barr-virus-associated nasopharyngeal carcinoma. Int J Cancer 72, 398–402.[CrossRef]
    [Google Scholar]
  46. Yoshizaki, T., Sato, H., Murono, S., Pagano, J. S. & Furukawa, M. ( 1999; ). Matrix metalloproteinase 9 is induced by the Epstein–Barr virus BZLF1 transactivator. Clin Exp Metastasis 17, 431–436.[CrossRef]
    [Google Scholar]
  47. Zeidler, R., Eissner, G., Meissner, P., Uebel, S., Tampe, R., Lazis, S. & Hammerschmidt, W. ( 1997; ). Downregulation of TAP1 in B lymphocytes by cellular and Epstein–Barr virus-encoded interleukin-10. Blood 90, 2390–2397.
    [Google Scholar]
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