title: 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.
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.
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden. lorand.kis@karolinska.se
authors.forename: Loránd L
authors.initials: LL
authors.lastname: Kis
authors.forename: Natalija
authors.initials: N
authors.lastname: Gerasimcik
authors.forename: Daniel
authors.initials: D
authors.lastname: Salamon
authors.forename: Emma K
authors.initials: EK
authors.lastname: Persson
authors.forename: Noémi
authors.initials: N
authors.lastname: Nagy
authors.forename: George
authors.initials: G
authors.lastname: Klein
authors.forename: Eva
authors.initials: E
authors.lastname: Severinson
authors.forename: Eva
authors.initials: E
authors.lastname: Klein
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001402:B-Lymphocytes / Q000378:metabolism; D001665:Binding Sites; D015153:Blotting, Western; D002051:Burkitt Lymphoma / Q000235:genetics / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D023201:CD40 Ligand / Q000378:metabolism; D002478:Cells, Cultured; D019309:Epstein-Barr Virus Nuclear Antigens / Q000378:metabolism*; D006689:Hodgkin Disease / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018793:Interleukin-13 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology*; D014066:Palatine Tonsil / Q000166:cytology / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D050800:STAT6 Transcription Factor / Q000378:metabolism*; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C402641:EBNA-2 protein, Human herpesvirus 4; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D019309:Epstein-Barr Virus Nuclear Antigens; D018793:Interleukin-13; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D014763:Viral Matrix Proteins; D014764:Viral Proteins; D023201:CD40 Ligand; D015847:Interleukin-4; C417029:EBV-encoded nuclear antigen 1