Role of NF-kappa B in cell survival and transcription of latent membrane protein 1-expressing or Epstein-Barr virus latency III-infected cells.
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 epsilon. 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, MIP1 beta, 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.
Cahir-McFarland
Ellen D
ED
The Channing Laboratory and Infectious Disease Division, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA. ecahir@rics.bwh.harvard.edu
Carter
Kara
K
Rosenwald
Andreas
A
Giltnane
Jena M
JM
Henrickson
Sarah E
SE
Staudt
Louis M
LM
Kieff
Elliott
E
D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology; D020869:Gene Expression Profiling; D005814:Genes, Viral; D004854:Herpesvirus 4, Human / Q000235:genetics / Q000472:pathogenicity* / Q000502:physiology; D006801:Humans; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D009570:Nitriles; D009930:Organic Chemicals / Q000494:pharmacology; D013450:Sulfones; D014158:Transcription, Genetic; D014763:Viral Matrix Proteins / Q000235:genetics*; D017735:Virus Latency; D048051:p38 Mitogen-Activated Protein Kinases
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D016328:NF-kappa B; D009570:Nitriles; D009930:Organic Chemicals; D013450:Sulfones; D014763:Viral Matrix Proteins; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases