title: The Epstein-Barr virus latent membrane protein 1 induces interleukin-10 in Burkitt's lymphoma cells but not in Hodgkin's cells involving the p38/SAPK2 pathway.
abstract: Infection of B cells with Epstein-Barr Virus (EBV) induces interleukin-10 (IL-10) production, which may contribute to transformation. IL-10 can modulate the immune response at certain levels, playing a crucial role in balancing humoral and cellular responses. Moreover, it can function as a growth and differentiation factor for B cells. However, the mechanism of IL-10 induction is still unclear. Here we demonstrate that IL-10 was specifically induced by the EBV-latent membrane protein 1 (LMP1) in Burkitt's lymphoma (BL) cell lines BL2 and BL41. In two T cell lines (Jurkat, MOLT3), two NHL cell lines (U266, MHH-PREB1), or three Hodgkin's disease (HD) cell lines (L428, L540, and KMH2), LMP1 did not induce IL-10 expression. In contrast, LMP1 activated CD40 or CD54 (ICAM1) expression in the analyzed cell lines. LMP1 derivatives lacking the C-terminal activation regions (CTAR), by deletion of the amino acids between 187 and 351 (Delta CTAR1) or 232 and 386 (Delta CTAR2), alone, or together induced IL-10 at very low amounts compared to wild-type LMP1. Inhibition of LMP1-mediated NF kappa B activation by constitutive repressive I kappa B-alpha only marginally impaired IL-10 expression in BL2 cells, while SB2035080 at 5 microM (a specific p38/SAPK2 inhibitor) led to reduced IL-10 expression. Our findings confirm the role of LMP1 in transactivation of cellular genes possibly important for tumor immunoescape but show that more than one signaling pathway is involved in this activation and suggests the necessity of a defined conformation of CTARs to activate IL-10 involving p38/SAPK2.
authors.affiliation: Klinik für Innere Medizin I, Zentrum für Molekulare Medizin, Universität zu Köln, D-50924 Cologne, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Vockerodt
authors.forename: B
authors.initials: B
authors.lastname: Haier
authors.forename: P
authors.initials: P
authors.lastname: Buttgereit
authors.forename: H
authors.initials: H
authors.lastname: Tesch
authors.forename: D
authors.initials: D
authors.lastname: Kube
mesh_terms: D001665:Binding Sites; D002051:Burkitt Lymphoma; D019013:CD40 Antigens / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression; D006689:Hodgkin Disease; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D018189:Immunomagnetic Separation; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000235:genetics; D019169:Jurkat Cells; D008223:Lymphoma; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008934:Mitogens / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D019014:fas Receptor / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D019013:CD40 Antigens; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D004791:Enzyme Inhibitors; D007093:Imidazoles; D008934:Mitogens; D016328:NF-kappa B; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D014763:Viral Matrix Proteins; D019014:fas Receptor; D018799:Intercellular Adhesion Molecule-1; D016753:Interleukin-10; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate; C093642:SB 203580