1887

Abstract

Epstein–Barr virus (EBV) latently infected B-cells are the precursors of EBV-associated malignancies. EBV-infection induces the production of pro-survival and anti-inflammatory cytokines that may be important in the transition between latency and malignancy. One EBV protein, LMP2A, can be detected in both latently infected resting B-cells and in EBV-associated malignancies. Therefore, we tested the ability of LMP2A to influence cytokine production using both LMP2A-Tg primary B-cells and LMP2A-expressing B-cell lines. Our data demonstrate that LMP2A does not globally alter B-cell-produced cytokine levels, but specifically targets IL-10. Additional studies using ELISA and real-time-RT-PCR confirm that LMP2A utilizes PI3-kinase to increase IL-10 levels. Finally, the data demonstrate that LMP2A-expressing B-cell lines are more dependent on IL-10 for survival in comparison to LMP2A-negative B-cell lines. These data identify a novel function of LMP2A in the alteration of a cytokine that is important for both tumour survival and anti-tumour responses.

Loading

Article metrics loading...

/content/journal/jgv/10.1099/vir.0.049221-0
2013-05-01
2024-04-19
Loading full text...

Full text loading...

/deliver/fulltext/jgv/94/5/1127.html?itemId=/content/journal/jgv/10.1099/vir.0.049221-0&mimeType=html&fmt=ahah

References

  1. Babcock G. J., Decker L. L., Volk M., Thorley-Lawson D. A. 1998; EBV persistence in memory B cells in vivo. Immunity 9:395–404 [View Article][PubMed]
    [Google Scholar]
  2. Babcock G. J., Hochberg D., Thorley-Lawson A. D. 2000; The expression pattern of Epstein–Barr virus latent genes in vivo is dependent upon the differentiation stage of the infected B cell. Immunity 13:497–506 [View Article][PubMed]
    [Google Scholar]
  3. Babcock G. J., Miyashita-Lin E. M., Thorley-Lawson D. A. 2001; Detection of EBV infection at the single-cell level. Precise quantitation of virus-infected cells in vivo. Methods Mol Biol 174:103–110[PubMed]
    [Google Scholar]
  4. Banchereau J., Blanchard D., Brière F., Galizzi J. P., Garrone P., Hermann P., Lebecque S., Rousset F. 1993; Role of cytokines in human B lymphocyte growth and differentiation. Nouv Rev Fr Hematol 35:61–66[PubMed]
    [Google Scholar]
  5. Beatty P. R., Krams S. M., Martinez O. M. 1997; Involvement of IL-10 in the autonomous growth of EBV-transformed B cell lines. J Immunol 158:4045–4051[PubMed]
    [Google Scholar]
  6. Bechtel D., Kurth J., Unkel C., Küppers R. 2005; Transformation of BCR-deficient germinal-center B cells by EBV supports a major role of the virus in the pathogenesis of Hodgkin and posttransplantation lymphomas. Blood 106:4345–4350 [View Article][PubMed]
    [Google Scholar]
  7. Bell A. I., Groves K., Kelly G. L., Croom-Carter D., Hui E., Chan A. T., Rickinson A. B. 2006; Analysis of Epstein–Barr virus latent gene expression in endemic Burkitt’s lymphoma and nasopharyngeal carcinoma tumour cells by using quantitative real-time PCR assays. J Gen Virol 87:2885–2890 [View Article][PubMed]
    [Google Scholar]
  8. Brennan P. 2001; Signalling events regulating lymphoid growth and survival. Semin Cancer Biol 11:415–421 [View Article][PubMed]
    [Google Scholar]
  9. Bultema R., Longnecker R., Swanson-Mungerson M. 2009; Epstein–Barr virus LMP2A accelerates MYC-induced lymphomagenesis. Oncogene 28:1471–1476 [View Article][PubMed]
    [Google Scholar]
  10. Burdin N., Van Kooten C., Galibert L., Abrams J. S., Wijdenes J., Banchereau J., Rousset F. 1995; Endogenous IL-6 and IL-10 contribute to the differentiation of CD40-activated human B lymphocytes. J Immunol 154:2533–2544[PubMed]
    [Google Scholar]
  11. Caldwell R. G., Wilson J. B., Anderson S. J., Longnecker R. 1998; Epstein–Barr virus LMP2A drives B cell development and survival in the absence of normal B cell receptor signals. Immunity 9:405–411 [View Article][PubMed]
    [Google Scholar]
  12. Cortes J., Kurzrock R. 1997; Interleukin-10 in non-Hodgkin’s lymphoma. Leuk Lymphoma 26:251–259[PubMed]
    [Google Scholar]
  13. de Waal Malefyt R., Abrams J., Bennett B., Figdor C. G., de Vries J. E. 1991; Interleukin 10 (IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J Exp Med 174:1209–1220 [View Article][PubMed]
    [Google Scholar]
  14. Decker L. L., Klaman L. D., Thorley-Lawson D. A. 1996; Detection of the latent form of Epstein–Barr virus DNA in the peripheral blood of healthy individuals. J Virol 70:3286–3289[PubMed]
    [Google Scholar]
  15. Enk A. H., Katz S. I. 1992; Identification and induction of keratinocyte-derived IL-10. J Immunol 149:92–95[PubMed]
    [Google Scholar]
  16. Fukuda M., Longnecker R. 2004; Latent membrane protein 2A inhibits transforming growth factor-beta 1-induced apoptosis through the phosphatidylinositol 3-kinase/Akt pathway. J Virol 78:1697–1705 [View Article][PubMed]
    [Google Scholar]
  17. Hatton O., Phillips L. K., Vaysberg M., Hurwich J., Krams S. M., Martinez O. M. 2011; Syk activation of phosphatidylinositol 3-kinase/Akt prevents HtrA2-dependent loss of X-linked inhibitor of apoptosis protein (XIAP) to promote survival of Epstein–Barr virus+ (EBV+) B cell lymphomas. J Biol Chem 286:37368–37378 [View Article][PubMed]
    [Google Scholar]
  18. Hochberg D., Middeldorp J. M., Catalina M., Sullivan J. L., Luzuriaga K., Thorley-Lawson D. A. 2004; Demonstration of the Burkitt’s lymphoma Epstein–Barr virus phenotype in dividing latently infected memory cells in vivo. Proc Natl Acad Sci U S A 101:239–244 [View Article][PubMed]
    [Google Scholar]
  19. Ikeda M., Longnecker R. 2007; Cholesterol is critical for Epstein–Barr virus latent membrane protein 2A trafficking and protein stability. Virology 360:461–468 [View Article][PubMed]
    [Google Scholar]
  20. Ikeda A., Merchant M., Lev L., Longnecker R., Ikeda M. 2004; Latent membrane protein 2A, a viral B cell receptor homologue, induces CD5+ B-1 cell development. J Immunol 172:5329–5337[PubMed] [CrossRef]
    [Google Scholar]
  21. Jochum S., Moosmann A., Lang S., Hammerschmidt W., Zeidler R. 2012; The EBV immunoevasins vIL-10 and BNLF2a protect newly infected B cells from immune recognition and elimination. PLoS Pathog 8:e1002704 [View Article][PubMed]
    [Google Scholar]
  22. Khatri V. P., Caligiuri M. A. 1998; A review of the association between interleukin-10 and human B-cell malignancies. Cancer Immunol Immunother 46:239–244 [View Article][PubMed]
    [Google Scholar]
  23. Konforte D., Paige C. J. 2009; Interleukin-21 regulates expression of the immediate-early lytic cycle genes and proteins in Epstein–Barr virus infected B cells. Virus Res 144:339–343 [View Article][PubMed]
    [Google Scholar]
  24. Lambert S. L., Martinez O. M. 2007; Latent membrane protein 1 of EBV activates phosphatidylinositol 3-kinase to induce production of IL-10. J Immunol 179:8225–8234[PubMed] [CrossRef]
    [Google Scholar]
  25. Liu Y., de Waal Malefyt R., Briere F., Parham C., Bridon J. M., Banchereau J., Moore K. W., Xu J. 1997; The EBV IL-10 homologue is a selective agonist with impaired binding to the IL-10 receptor. J Immunol 158:604–613[PubMed]
    [Google Scholar]
  26. Longnecker R., Miller C. L., Miao X. Q., Marchini A., Kieff E. 1992; The only domain which distinguishes Epstein–Barr virus latent membrane protein 2A (LMP2A) from LMP2B is dispensable for lymphocyte infection and growth transformation in vitro; LMP2A is therefore nonessential. J Virol 66:6461–6469[PubMed]
    [Google Scholar]
  27. Mancao C., Hammerschmidt W. 2007; Epstein–Barr virus latent membrane protein 2A is a B-cell receptor mimic and essential for B-cell survival. Blood 110:3715–3721 [View Article][PubMed]
    [Google Scholar]
  28. Miller C. L., Longnecker R., Kieff E. 1993; Epstein–Barr virus latent membrane protein 2A blocks calcium mobilization in B lymphocytes. J Virol 67:3087–3094[PubMed]
    [Google Scholar]
  29. Mizoguchi A., Bhan A. K. 2006; A case for regulatory B cells. J Immunol 176:705–710[PubMed] [CrossRef]
    [Google Scholar]
  30. Niedobitek G., Agathanggelou A., Herbst H., Whitehead L., Wright D. H., Young L. S. 1997; Epstein–Barr virus (EBV) infection in infectious mononucleosis: virus latency, replication and phenotype of EBV-infected cells. J Pathol 182:151–159 [View Article][PubMed]
    [Google Scholar]
  31. O’Garra A., Howard M. 1992; Cytokines and Ly-1 (B1) B cells. Int Rev Immunol 8:219–234 [View Article][PubMed]
    [Google Scholar]
  32. O’Garra A., Vieira P. 2007; T(H)1 cells control themselves by producing interleukin-10. Nat Rev Immunol 7:425–428 [View Article][PubMed]
    [Google Scholar]
  33. O’Garra A., Stapleton G., Dhar V., Pearce M., Schumacher J., Rugo H., Barbis D., Stall A., Cupp J. other authors 1990; Production of cytokines by mouse B cells: B lymphomas and normal B cells produce interleukin 10. Int Immunol 2:821–832 [View Article][PubMed]
    [Google Scholar]
  34. Portis T., Longnecker R. 2004; Epstein–Barr virus (EBV) LMP2A mediates B-lymphocyte survival through constitutive activation of the Ras/PI3K/Akt pathway. Oncogene 23:8619–8628 [View Article][PubMed]
    [Google Scholar]
  35. Rochford R., Miller C. L., Cannon M. J., Izumi K. M., Kieff E., Longnecker R. 1997; In vivo growth of Epstein–Barr virus transformed B cells with mutations in latent membrane protein 2 (LMP2). Arch Virol 142:707–720 [View Article][PubMed]
    [Google Scholar]
  36. Rode H. J., Bugert J. J., Handermann M., Schnitzler P., Kehm R., Janssen W., Delius H., Darai G. 1994; Molecular characterization and determination of the coding capacity of the genome of equine herpesvirus type 2 between the genome coordinates 0.235 and 0.258 (the EcoRI DNA fragment N; 4.2 kbp). Virus Genes 9:61–75 [View Article][PubMed]
    [Google Scholar]
  37. Samanta M., Iwakiri D., Takada K. 2008; Epstein–Barr virus-encoded small RNA induces IL-10 through RIG-I-mediated IRF-3 signaling. Oncogene 27:4150–4160 [View Article][PubMed]
    [Google Scholar]
  38. Saraiva M., O’Garra A. 2010; The regulation of IL-10 production by immune cells. Nat Rev Immunol 10:170–181 [View Article][PubMed]
    [Google Scholar]
  39. Swanson-Mungerson M., Bultema R., Longnecker R. 2006; Epstein–Barr virus LMP2A enhances B-cell responses in vivo and in vitro. J Virol 80:6764–6770 [View Article][PubMed]
    [Google Scholar]
  40. Swanson-Mungerson M., Bultema R., Longnecker R. 2010; Epstein–Barr virus LMP2A imposes sensitivity to apoptosis. J Gen Virol 91:2197–2202 [View Article][PubMed]
    [Google Scholar]
  41. Tsai S. C., Lin S. J., Chen P. W., Luo W. Y., Yeh T. H., Wang H. W., Chen C. J., Tsai C. H. 2009; EBV Zta protein induces the expression of interleukin-13, promoting the proliferation of EBV-infected B cells and lymphoblastoid cell lines. Blood 114:109–118 [View Article][PubMed]
    [Google Scholar]
  42. 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 [View Article][PubMed]
    [Google Scholar]
  43. Yoon S. I., Jones B. C., Logsdon N. J., Harris B. D., Kuruganti S., Walter M. R. 2012; Epstein–Barr virus IL-10 engages IL-10R1 by a two-step mechanism leading to altered signaling properties. J Biol Chem 287:26586–26595 [View Article][PubMed]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/vir.0.049221-0
Loading
/content/journal/jgv/10.1099/vir.0.049221-0
Loading

Data & Media loading...

Supplements

Supplementary material 1

PDF
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