Epstein-Barr virus modulates host cell microRNA-194 to promote IL-10 production and B lymphoma cell survival

Am J Transplant. 2015 Nov;15(11):2814-24. doi: 10.1111/ajt.13375. Epub 2015 Jul 3.

Abstract

Epstein-Barr virus (EBV) is a γ-herpesvirus that is linked to the development of posttransplant lymphoproliferative disorder (PTLD) in solid organ recipients. We previously demonstrated that EBV(+) B cell lymphoma cell lines isolated from patients with PTLD produce human IL-10 as an autocrine growth factor. However, little is known regarding IL-10 regulation in B cells. Here we show that EBV infection markedly alters the expression of host B cell microRNA, a class of small noncoding RNA that is an important regulator of transcriptional and posttranscriptional gene expression. Gene arrays reveal unique microRNA profiles in EBV(+) B cell lymphoma lines from patients with PTLD, compared to normal B cells or in vitro generated EBV(+) lymphoblastoid cell lines. We show that microRNA-194 expression is uniquely suppressed in EBV(+) B cell lines from PTLD patients and that the 3'untranslated region of IL-10 is targeted by microRNA-194. Overexpression of microRNA-194 attenuates IL-10 production and increases apoptosis of EBV(+) B cell lymphoma lines. Together, these data indicate that EBV co-opts the host B cell microRNA network and specifically suppresses microRNA-194 to override control of IL-10 expression. Thus, modulation of microRNA-194 may constitute a novel approach to inhibiting proliferation of EBV(+) B cell lymphomas in PTLD.

Keywords: Cellular biology; infectious disease; molecular biology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • B-Lymphocytes / pathology
  • Cell Survival
  • Epstein-Barr Virus Infections / pathology
  • Epstein-Barr Virus Infections / virology*
  • Gene Expression Regulation, Neoplastic
  • Herpesvirus 4, Human / genetics*
  • Humans
  • Interleukin-10 / metabolism*
  • Lymphoma, B-Cell / genetics
  • Lymphoma, B-Cell / pathology*
  • Lymphoproliferative Disorders / pathology
  • Lymphoproliferative Disorders / virology*
  • MicroRNAs / metabolism
  • Organ Transplantation / adverse effects
  • Real-Time Polymerase Chain Reaction / methods
  • Reference Values
  • Tumor Cells, Cultured

Substances

  • IL10 protein, human
  • MicroRNAs
  • Interleukin-10