IL-10 can induce the expression of EBV-encoded latent membrane protein-1 (LMP-1) in the absence of EBNA-2 in B lymphocytes and in Burkitt lymphoma- and NK lymphoma-derived cell lines

Kis, Lóránd; Takahara, Miki; Nagy, Noémi; Klein, George; Klein, Eva

doi:10.1182/blood-2005-06-2569

Cited by 71 publications

(60 citation statements)

References 54 publications

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“…We showed previously that IL-10 could induce the expression of LMP-1 in the absence of EBNA-2 in type I BL and NK lymphoma cell lines (23). Because both IL-10 and IL-21 potently activated STAT3, the LMP-1-inducing effect of the two cytokines probably converges on STAT3.…”

Section: Resultsmentioning

confidence: 88%

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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

Kis

Salamon

Persson

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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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 EBVassociated 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.Epstein-Barr virus | IL-21 | lymphoma | STAT3

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Section: Resultsmentioning

confidence: 88%

“…More detailed information on the origin of the cell lines can be found in ref. 23. The ER/EB2-5 cells were kindly provided by G. W. Bornkamm (German Research Center for Environmental Health, Institute of Clinical Molecular Biology and Tumor Genetics, Munich).…”

Section: Methodsmentioning

confidence: 99%

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

Salamon

Persson

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…18 The following BL lines were studied: the type I Mutu I cl.216, cl.59, cl.148, 19 Jijoye M13; the type III Mutu III cl.99 and cl.176, 19 Raji, Jijoye P79; BLs with an EBNA-2-deleted EBV strain Daudi and P3HR1. 20 The KMH2 cells infected with the Akata-Neo strain (KMH2-EBV), made in our laboratory, were previously reported. 17 A similar pair of EBV-negative and -positive KMH2 cells (KMH2(PM) and KMH2-EBV(PM) in this study) were kindly provided by Karl R. N. Baumforth and Paul G. Murray 21 (CRUK Institute for Cancer Studies, University of Birmingham).…”

Section: Cell Lines and Cell Culturementioning

confidence: 99%

STAT6 signaling pathway activated by the cytokines IL-4 and IL-13 induces expression of the Epstein-Barr virus–encoded protein LMP-1 in absence of EBNA-2: implications for the type II EBV latent gene expression in Hodgkin lymphoma

Kis

Gerasimčik

Salamon

et al. 2011

Blood

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IntroductionEpstein-Barr virus (EBV) is a ␥-herpes virus of the Lymphocryptovirus genus that has succeeded to colonize Ͼ 90% of the adult population. 1 As a general characteristic of these viruses, they can all infect and immortalize B-lymphocytes in vitro. The in vitro EBV-infected B cells proliferate and give rise to lymphoblastoid cell lines (LCLs). The pattern of latent EBV gene expression seen in LCLs is referred to as the type III latency, in which 9 virally encoded proteins are expressed (EBV nuclear antigen 1-6 [EBNA1-6], Latent Membrane Protein-1 [LMP-1], LMP-2A, and LMP-2B). 1 Similarly to the EBV gene expression seen in LCLs, type III latent B cells were found in healthy persons during the primary infection 2 and the virus carrier state. 3 These cells are highly immunogenic and are eliminated by the cellular immune response. 4 After the primary infection the virus establishes a life-long infection in the memory B-cell reservoir, from where it is thought to reactivate and produce new progeny that are shed in the saliva. 1,5 In immunodeficient states, in which the cellular immune responses are compromised, the EBV-infected type III B cells can give rise to lymphoproliferations/lymphomas, as seen in the posttransplantation lymphoproliferations 6,7 and some AIDS lymphomas. 8 Depending on the histologic origin, the activation state, and the differentiation stage of the virus-carrying cells, EBV can adopt other viral gene expression patterns as well. 9 This is evidenced by the type I EBV gene expression seen in Burkitt lymphomas (BLs), primary effusion lymphomas, 10 and diffuse large B-cell lymphomas, whereby EBNA-1 is the only viral protein expressed. However, EBNA-1 is coexpressed with LMP-1 and LMP-2 in the EBV-carrying classical HL (cHL 11 ; type II latency), nasal natural killer/T-cell lymphoma, 12,13 some nasopharyngeal carcinomas (NPCs), 14,15 and peripheral T-cell lymphomas. 16 The expression of LMP-1 in type III latency is driven by the EBNA-2 protein. 1 The molecular mechanism of LMP-1 expression in type II latent cells, thus in the absence of EBNA-2, is only partially known. EBV-positive cHL is unique among the type II malignancies because all the Hodgkin/Reed-Sternberg (HRS) cells express high levels of LMP-1, whereas LMP-1 expression is heterogeneous in other tumors. 15 Not just the mechanism of LMP-1 expression in the HRS cells is unknown, but it is still an open question whether LMP-1 is needed for the survival or proliferation of these malignant cells. Although the type II EBV latency is seen in a proportion of cHLs, the available HL-derived cell lines are EBV negative. Thus, there is no in vitro system in which this type of virus-cell interaction can be studied.We have previously reported that exposure of the in vitro EBV-converted HL-derived cell line KMH2-EBV to CD40 ligand (CD40L) and interleukin-4 (IL-4) led to EBNA-2-independent expression of LMP-1. 17 In the continuation of this work we identify now IL-4, IL-13, and CD40L as potent inducers of LMP-1 not only Submitted January 21, 2010...

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“…It has been implicated in the pathogenesis and tumor progression in several human malignancies, including Burkitt's and Hodgkin's lymphomas, gastric carcinoma and nasopharyngeal carcinoma (NPC) (Lindahl et al, 1974;Kis et al, 2006;Queiroga et al, 2008). EBV infection is mainly characterized by the expression of latent genes including nuclear antigens (EBNAs), latent membrane proteins (LMPs) and EBV-encoded RNA (EBER) (Munz and Moormann, 2008;Thorley-Lawson and Allday, 2008) under strict, host-cell-dependent transcriptional control.…”

Section: Introductionmentioning

confidence: 99%

Functional interaction of Ugene and EBV infection mediates tumorigenic effects

et al. 2011

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Epstein-Barr virus (EBV) infection is associated with many human neoplasms, in which EBV-derived latent membrane protein-1 (LMP1) appears to be critical, but its exact oncogenic mechanism remains to be defined. To this end, our initial microarray analyses identified a LMP1-inducible gene, Ugene, originally characterized as a binding partner for uracil DNA glycosylase 2, which is highly expressed in malignant colon cancer. In this report, it was found that Ugene, designated herein as LMP1-induced protein (LMPIP), was induced, in a time-dependent manner, in EBV-infected peripheral blood mononuclear cells and LMP1-transfected 293 cells. Functionally, when compared with mock-transfected cells, overexpression of LMPIP in nasopharyngeal carcinoma (NPC) cell lines resulted in a decrease in reactive oxygen species production and maintained mitochondria membrane potential (Dw) loss induced by H 2 O 2 . The NPC cells transfected with LMPIP also showed a decrease in G1 population and an increase in the cell population in sub-G1 and multiploid phase, concomitant with increased levels of cell cycle activators, including cyclin D1 and CDK4. In contrast, silencing of LMPIP expression in the NPC tumor cell lines with short hairpin RNA interference revealed significantly decreased cell population at G1/S phase, while the number of cells in multiploid phase increased. Significantly, NPC cells with LMPIP knock-down also showed a decrease in tumorigenic and transforming activity induced by ectopic LMP1 expression, as determined by analyses of soft agar foci and tumor size in nude mice. Further, elevated LMPIP expression was also noted in cytoplasm and nuclei in EBVinfected NPC tumor cell mass and non-EBV-infected tumor cell lines. These results suggested that LMPIP may have an important mediator role in EBV-mediated neoplasm and may serve as a new target for therapy of tumors induced by EBV infection.

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IL-10 can induce the expression of EBV-encoded latent membrane protein-1 (LMP-1) in the absence of EBNA-2 in B lymphocytes and in Burkitt lymphoma- and NK lymphoma-derived cell lines

Cited by 71 publications

References 54 publications

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

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

STAT6 signaling pathway activated by the cytokines IL-4 and IL-13 induces expression of the Epstein-Barr virus–encoded protein LMP-1 in absence of EBNA-2: implications for the type II EBV latent gene expression in Hodgkin lymphoma

Functional interaction of Ugene and EBV infection mediates tumorigenic effects

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