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.
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.
Kis
Loránd L
LL
Department of Microbiology, Karolinska Institutet, S-171 77 Stockholm, Sweden.
Salamon
Daniel
D
Persson
Emma K
EK
Nagy
Noémi
N
Scheeren
Ferenc A
FA
Spits
Hergen
H
Klein
George
G
Klein
Eva
E
D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000821:virology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D019309:Epstein-Barr Virus Nuclear Antigens / Q000494:pharmacology; D015967:Gene Expression Regulation, Viral / Q000187:drug effects*; D016679:Genome, Viral; D004854:Herpesvirus 4, Human / Q000235:genetics*; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000187:drug effects / Q000235:genetics; D007378:Interleukins / Q000494:pharmacology*; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000473:pathology / Q000821:virology; D009369:Neoplasms / Q000235:genetics / Q000821:virology; D011401:Promoter Regions, Genetic / Q000187:drug effects; D014763:Viral Matrix Proteins / Q000187:drug effects / Q000235:genetics* / Q000494:pharmacology; D014764:Viral Proteins / Q000494:pharmacology; D017735:Virus Latency / Q000235:genetics; D000098546:Interleukin-21
C402641:EBNA-2 protein, Human herpesvirus 4; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D019309:Epstein-Barr Virus Nuclear Antigens; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D007378:Interleukins; D014763:Viral Matrix Proteins; D014764:Viral Proteins; D000098546:Interleukin-21; C417029:EBV-encoded nuclear antigen 1