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IL-21 imposes a type II EBV gene expression on type III and type I B cells by the repression of C- and activation of LMP-1-promoter.
Proc Natl Acad Sci U S A. 2010 Jan 12; 107(2):872-7.PN

Abstract

Epstein-Barr virus (EBV) is associated with a variety of human tumors. Although the EBV-infected normal B cells in vitro and the EBV-carrying B cell lymphomas in immunodeficient patients express the full set of latent proteins (type III latency), the majority of EBV-associated malignancies express the restricted type I (EBNA-1 only) or type II (EBNA-1 and LMPs) viral program. The mechanisms responsible for these different latent viral gene expression patterns are only partially known. IL-21 is a potent B cell activator and plasma cell differentiation-inducer cytokine produced by CD4(+) T cells. We studied its effect on EBV-carrying B cells. In type I Burkitt lymphoma (BL) cell lines and in the conditional lymphoblastoid cell line (LCL) ER/EB2-5, IL-21 potently activated STAT3 and induced the expression of LMP-1, but not EBNA-2. The IL-21-treated type I Jijoye M13 BL line ceased to proliferate, and this was paralleled by the induction of IRF4 and the down-regulation of BCL6 expression. In the type III LCLs and BL lines, IL-21 repressed the C-promoter-derived and LMP-2A mRNAs, whereas it up-regulated the expression of LMP-1 mRNAs. The IL-21-treated type III cells underwent plasma cell differentiation with the induction of Blimp-1, and high levels of Ig and Oct-2. IL-21 might be involved in the EBNA-2-independent expression of LMP-1 in EBV-carrying type II cells. In light of the fact that IL-21 is already in clinical trials for the treatment of multiple malignancies, the in vivo modulation of EBV gene expression by IL-21 might have therapeutic benefits for the EBV-carrying malignancies.

Authors+Show Affiliations

Department of Microbiology, Karolinska Institutet, S-171 77 Stockholm, Sweden.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20080768

Citation

Kis, Loránd L., et al. "IL-21 Imposes a Type II EBV Gene Expression On Type III and Type I B Cells By the Repression of C- and Activation of LMP-1-promoter." Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 2, 2010, pp. 872-7.
Kis LL, Salamon D, Persson EK, et al. IL-21 imposes a type II EBV gene expression on type III and type I B cells by the repression of C- and activation of LMP-1-promoter. Proc Natl Acad Sci U S A. 2010;107(2):872-7.
Kis, L. L., Salamon, D., Persson, E. K., Nagy, N., Scheeren, F. A., Spits, H., Klein, G., & Klein, E. (2010). IL-21 imposes a type II EBV gene expression on type III and type I B cells by the repression of C- and activation of LMP-1-promoter. Proceedings of the National Academy of Sciences of the United States of America, 107(2), 872-7. https://doi.org/10.1073/pnas.0912920107
Kis LL, et al. IL-21 Imposes a Type II EBV Gene Expression On Type III and Type I B Cells By the Repression of C- and Activation of LMP-1-promoter. Proc Natl Acad Sci U S A. 2010 Jan 12;107(2):872-7. PubMed PMID: 20080768.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - IL-21 imposes a type II EBV gene expression on type III and type I B cells by the repression of C- and activation of LMP-1-promoter. AU - Kis,Loránd L, AU - Salamon,Daniel, AU - Persson,Emma K, AU - Nagy,Noémi, AU - Scheeren,Ferenc A, AU - Spits,Hergen, AU - Klein,George, AU - Klein,Eva, Y1 - 2009/12/22/ PY - 2010/1/19/entrez PY - 2010/1/19/pubmed PY - 2010/2/27/medline SP - 872 EP - 7 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc Natl Acad Sci U S A VL - 107 IS - 2 N2 - Epstein-Barr virus (EBV) is associated with a variety of human tumors. Although the EBV-infected normal B cells in vitro and the EBV-carrying B cell lymphomas in immunodeficient patients express the full set of latent proteins (type III latency), the majority of EBV-associated malignancies express the restricted type I (EBNA-1 only) or type II (EBNA-1 and LMPs) viral program. The mechanisms responsible for these different latent viral gene expression patterns are only partially known. IL-21 is a potent B cell activator and plasma cell differentiation-inducer cytokine produced by CD4(+) T cells. We studied its effect on EBV-carrying B cells. In type I Burkitt lymphoma (BL) cell lines and in the conditional lymphoblastoid cell line (LCL) ER/EB2-5, IL-21 potently activated STAT3 and induced the expression of LMP-1, but not EBNA-2. The IL-21-treated type I Jijoye M13 BL line ceased to proliferate, and this was paralleled by the induction of IRF4 and the down-regulation of BCL6 expression. In the type III LCLs and BL lines, IL-21 repressed the C-promoter-derived and LMP-2A mRNAs, whereas it up-regulated the expression of LMP-1 mRNAs. The IL-21-treated type III cells underwent plasma cell differentiation with the induction of Blimp-1, and high levels of Ig and Oct-2. IL-21 might be involved in the EBNA-2-independent expression of LMP-1 in EBV-carrying type II cells. In light of the fact that IL-21 is already in clinical trials for the treatment of multiple malignancies, the in vivo modulation of EBV gene expression by IL-21 might have therapeutic benefits for the EBV-carrying malignancies. SN - 1091-6490 UR - https://www.unboundmedicine.com/medline/citation/20080768/IL_21_imposes_a_type_II_EBV_gene_expression_on_type_III_and_type_I_B_cells_by_the_repression_of_C__and_activation_of_LMP_1_promoter_ L2 - http://www.pnas.org/cgi/pmidlookup?view=long&pmid=20080768 DB - PRIME DP - Unbound Medicine ER -