Inhibition of p38 MAP kinase pathway induces apoptosis and prevents Epstein Barr virus reactivation in Raji cells exposed to lytic cycle inducing compounds.
BACKGROUND
EBV lytic cycle activators, such as phorbol esters, anti-immunoglobulin, transforming growth factor beta (TGFbeta), sodium butyrate, induce apoptosis in EBV-negative but not in EBV-positive Burkitt's lymphoma (BL) cells. To investigate the molecular mechanisms allowing EBV-infected cells to be protected, we examined the expression of viral and cellular antiapoptotic proteins as well as the activation of signal transduction pathways in BL-derived Raji cells exposed to lytic cycle inducing agents.


RESULTS
Our data show that, following EBV activation, the latent membrane protein 1 (LMP1) and the cellular anti-apoptotic proteins MCL-1 and BCL-2 were quickly up-regulated and that Raji cells remained viable even when exposed simultaneously to P(BU)(2), sodium butyrate and TGFbeta. We report here that inhibition of p38 pathway, during EBV activation, led to a three fold increment of apoptosis and largely prevented lytic gene expression.


CONCLUSIONS
These findings indicate that, during the switch from the latent to the lytic phase of EBV infection, p38 MAPK phosphorylation plays a key role both for protecting the host cells from apoptosis as well as for inducing viral reactivation. Because Raji cells are defective for late antigens expression, we hypothesize that the increment of LMP1 gene expression in the early phases of EBV lytic cycle might contribute to the survival of the EBV-positive cells.
Matusali
Giulia
G
Department of Public Health Sciences, University La Sapienza, Rome, Italy. giuliamat@hotmail.com
Arena
Giuseppe
G
De Leo
Alessandra
A
Di Renzo
Livia
L
Mattia
Elena
E
D017209:Apoptosis; D015153:Blotting, Western; D002051:Burkitt Lymphoma; D045744:Cell Line, Tumor; D024202:Electrophoretic Mobility Shift Assay; D005434:Flow Cytometry; D004854:Herpesvirus 4, Human / Q000502:physiology*; D006801:Humans; D008856:Microscopy, Fluorescence; D010703:Phorbol Esters / Q000494:pharmacology; D017382:Reactive Oxygen Species; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014775:Virus Activation / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D010703:Phorbol Esters; D017382:Reactive Oxygen Species; D016212:Transforming Growth Factor beta; D048051:p38 Mitogen-Activated Protein Kinases