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Journal of Virology, April 2004, p. 4108-4119, Vol. 78, No. 8
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.8.4108-4119.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Role of NF-{kappa}B in Cell Survival and Transcription of Latent Membrane Protein 1-Expressing or Epstein-Barr Virus Latency III-Infected Cells

Ellen D. Cahir-McFarland,1* Kara Carter,1,{dagger} Andreas Rosenwald,2 Jena M. Giltnane,2 Sarah E. Henrickson,2 Louis M. Staudt,2 and Elliott Kieff1

The Channing Laboratory and Infectious Disease Division, Brigham and Women's Hospital, and Departments of Medicine and of Microbiology and Molecular Genetics, Harvard Medical School, Boston, Massachusetts 02115,1 Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 208922

Received 26 August 2003/ Accepted 15 December 2003

Epstein-Barr virus (EBV) latency III infection converts B lymphocytes into lymphoblastoid cell lines (LCLs) by expressing EBV nuclear and membrane proteins, EBNAs, and latent membrane proteins (LMPs), which regulate transcription through Notch and tumor necrosis factor receptor pathways. The role of NF-{kappa}B in LMP1 and overall EBV latency III transcriptional effects was investigated by treating LCLs with BAY11-7082 (BAY11). BAY11 rapidly and irreversibly inhibited NF-{kappa}B, decreased mitochondrial membrane potential, induced apoptosis, and altered LCL gene expression. BAY11 effects were similar to those of an NF-{kappa}B inhibitor, {Delta}N-I{kappa}B{alpha}, in effecting decreased JNK1 expression and in microarray analyses. More than 80% of array elements that decreased with {Delta}N-I{kappa}B{alpha} expression decreased with BAY11 treatment. Newly identified NF-{kappa}B-induced, LMP1-induced, and EBV-induced genes included pleckstrin, Jun-B, c-FLIP, CIP4, and I{kappa}B{varepsilon}. Of 776 significantly changed array elements, 134 were fourfold upregulated in EBV latency III, and 74 were fourfold upregulated with LMP1 expression alone, whereas only 28 were more than fourfold downregulated by EBV latency III. EBV latency III-regulated gene products mediate cell migration (EBI2, CCR7, RGS1, RANTES, MIP1{alpha}, MIP1ß, CXCR5, and RGS13), antigen presentation (major histocompatibility complex proteins and JAW1), mitogen-activated protein kinase pathway (DUSP5 and p62Dok), and interferon (IFN) signaling (IFN-{gamma}R{alpha}, IRF-4, and STAT1). Comparison of EBV latency III LCL gene expression to immunoglobulin M (IgM)-stimulated B cells, germinal-center B cells, and germinal-center-derived lymphomas clustered LCLs with IgM-stimulated B cells separately from germinal-center cells or germinal-center lymphoma cells. Expression of IRF-2, AIM1, ASK1, SNF2L2, and components of IFN signaling pathways further distinguished EBV latency III-infected B cells from IgM-stimulated or germinal-center B cells.

* Corresponding author. Mailing address: Channing Laboratory and Infectious Disease Division, Brigham and Women's Hospital, Boston, MA 02130. Phone: (617) 525-4263. Fax: (617) 525-4251. E-mail: ecahir{at}rics.bwh.harvard.edu.

{dagger} Present address: Praecis Pharmaceuticals, Waltham, MA 02451.

Journal of Virology, April 2004, p. 4108-4119, Vol. 78, No. 8
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.8.4108-4119.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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