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

Loránd L. Kis, Natalija Gerasimčik, D. Salamon, Emma K. Persson, Noémi Nagy, George Klein, Eva Severinson, Eva Klein

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

In line with the B-lymphotropic nature of Epstein-Barr virus (EBV), the virus is present in several types of B-cell lymphomas. EBV expresses a different set of latent genes in the associated tumors, such as EBV nuclear antigen 1 (EBNA-1) and latent membrane proteins (LMPs; type II latency) in classical Hodgkin lymphomas (HLs). We previously reported that exposure of in vitro EBV-converted, HL-derived cell line KMH2-EBV to CD40-ligand and interleukin-4 (IL-4) induced the expression of LMP-1. Here, we show that exposure to IL-4 or IL-13 alone induced LMP-1 in the absence of EBNA-2. Induction of LMP-1 by IL-4 and IL-13 was mediated by the signal transducer signal transducer and activator of transcription 6 (STAT6) and a newly defined high-affinity STAT6-binding site in the LMP-1 promoter. IL-4 induced LMP-1 also in Burkitt lymphoma-derived lines and in tonsillar B cells infected with the EBNA-2-deficient EBV strain P3HR-1. Furthermore, coculture of EBV-carrying Burkitt lymphoma cells with activated CD4+ T cells resulted in the induction of LMP-1 in the absence of EBNA-2. Because Hodgkin/Reed-Sternberg cells are known to secrete IL-13, to have constitutively activated STAT6, and to be closely surrounded by CD4+ T cells, these mechanisms may be involved in the expression of LMP-1 in EBV-positive chronic HLs.

Original languageEnglish
Pages (from-to)165-174
Number of pages10
JournalBlood
Volume117
Issue number1
DOIs
Publication statusPublished - Jan 6 2011

Fingerprint

STAT6 Transcription Factor
Interleukin-13
Human Herpesvirus 4
Hodgkin Disease
Viruses
Gene expression
Interleukin-4
Cytokines
Gene Expression
Proteins
Burkitt Lymphoma
T-cells
Cells
Epstein-Barr Virus Nuclear Antigens
Reed-Sternberg Cells
T-Lymphocytes
CD40 Ligand
B-Cell Lymphoma
Coculture Techniques
Epstein-Barr virus EBV-associated membrane antigen

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

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, Loránd L.; Gerasimčik, Natalija; Salamon, D.; Persson, Emma K.; Nagy, Noémi; Klein, George; Severinson, Eva; Klein, Eva.

In: Blood, Vol. 117, No. 1, 06.01.2011, p. 165-174.

Research output: Contribution to journalArticle

Kis, Loránd L. ; Gerasimčik, Natalija ; Salamon, D. ; Persson, Emma K. ; Nagy, Noémi ; Klein, George ; Severinson, Eva ; Klein, Eva. / 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. In: Blood. 2011 ; Vol. 117, No. 1. pp. 165-174.
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AU - Kis, Loránd L.

AU - Gerasimčik, Natalija

AU - Salamon, D.

AU - Persson, Emma K.

AU - Nagy, Noémi

AU - Klein, George

AU - Severinson, Eva

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AB - In line with the B-lymphotropic nature of Epstein-Barr virus (EBV), the virus is present in several types of B-cell lymphomas. EBV expresses a different set of latent genes in the associated tumors, such as EBV nuclear antigen 1 (EBNA-1) and latent membrane proteins (LMPs; type II latency) in classical Hodgkin lymphomas (HLs). We previously reported that exposure of in vitro EBV-converted, HL-derived cell line KMH2-EBV to CD40-ligand and interleukin-4 (IL-4) induced the expression of LMP-1. Here, we show that exposure to IL-4 or IL-13 alone induced LMP-1 in the absence of EBNA-2. Induction of LMP-1 by IL-4 and IL-13 was mediated by the signal transducer signal transducer and activator of transcription 6 (STAT6) and a newly defined high-affinity STAT6-binding site in the LMP-1 promoter. IL-4 induced LMP-1 also in Burkitt lymphoma-derived lines and in tonsillar B cells infected with the EBNA-2-deficient EBV strain P3HR-1. Furthermore, coculture of EBV-carrying Burkitt lymphoma cells with activated CD4+ T cells resulted in the induction of LMP-1 in the absence of EBNA-2. Because Hodgkin/Reed-Sternberg cells are known to secrete IL-13, to have constitutively activated STAT6, and to be closely surrounded by CD4+ T cells, these mechanisms may be involved in the expression of LMP-1 in EBV-positive chronic HLs.

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