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

Loránd L. Kis, D. Salamon, Emma K. Persson, Noémi Nagy, Ferenc A. Scheeren, Hergen Spits, George Klein, Eva Klein

Research output: Contribution to journalArticle

51 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)872-877
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number2
DOIs
Publication statusPublished - 2010

Fingerprint

Human Herpesvirus 4
B-Lymphocytes
Gene Expression
Burkitt Lymphoma
Plasma Cells
Cell Differentiation
Neoplasms
Cell Line
Messenger RNA
Viral Genes
interleukin-21
B-Cell Lymphoma
Down-Regulation
Clinical Trials
Cytokines
T-Lymphocytes
Therapeutics
EBV-encoded nuclear antigen 1
Proteins

Keywords

  • Epstein-Barr virus
  • IL-21
  • Lymphoma
  • STAT3

ASJC Scopus subject areas

  • General

Cite this

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. / Kis, Loránd L.; Salamon, D.; Persson, Emma K.; Nagy, Noémi; Scheeren, Ferenc A.; Spits, Hergen; Klein, George; Klein, Eva.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 2, 2010, p. 872-877.

Research output: Contribution to journalArticle

Kis, Loránd L. ; Salamon, D. ; Persson, Emma K. ; Nagy, Noémi ; Scheeren, Ferenc A. ; Spits, Hergen ; Klein, George ; Klein, Eva. / 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. In: Proceedings of the National Academy of Sciences of the United States of America. 2010 ; Vol. 107, No. 2. pp. 872-877.
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AU - Kis, Loránd L.

AU - Salamon, D.

AU - Persson, Emma K.

AU - Nagy, Noémi

AU - Scheeren, Ferenc A.

AU - Spits, Hergen

AU - Klein, George

AU - Klein, Eva

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AB - 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.

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