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Journal of Virology, April 2005, p. 4936-4943, Vol. 79, No. 8
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.8.4936-4943.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Latent Membrane Protein 1 Regulates STAT1 through NF-{kappa}B-Dependent Interferon Secretion in Epstein-Barr Virus-Immortalized B Cells

Imen Najjar,1 Fanny Baran-Marszak,2 Christophe Le Clorennec,3 Christelle Laguillier,2 Olivier Schischmanoff,1 Ibtissam Youlyouz-Marfak,3 Martin Schlee,4 Georg W. Bornkamm,4 Martine Raphaël,2 Jean Feuillard,3 and Remi Fagard1*

Université Paris 13, UPRES EA 3406, Service de Biochimie AP-HP Hôpital Avicenne, Bobigny,1 INSERM E109, Université Paris 11, Service d'Hématologie, Hôpital Kremlin-Bicêtre, Le Kremlin-Bicêtre,2 CNRS UMR 6101 and Laboratoire d'Hématologie, Université de Limoges, Faculté de Médecine, CHU Dupuytren, Limoges, France,3 GSF-Institute of Clinical Molecular Biology and Tumor Genetics, Munich, Germany4

Received 13 July 2004/ Accepted 26 October 2004

Constitutive activation of signal transducer and activator of transcription 1 (STAT1) is a distinctive feature of Epstein-Barr virus (EBV)-immortalized B cells (lymphoblastoid cell lines [LCLs]). The expression of STAT1 in these cells is modulated by the latent membrane protein 1 (LMP1), but the mechanism of STAT1 activation has remained unclear. We demonstrate that the tyrosine phosphorylation of STAT1 in LCLs results from an indirect pathway encompassing an NF-{kappa}B-dependent secretion of interferons (IFNs). The cell culture supernatant of LCLs induced tyrosine phosphorylation of STAT1 in cells with no constitutively activated STAT1. Moreover, removal of supernatant from LCLs was sufficient to decrease the phosphorylation of STAT1. Inhibition of NF-{kappa}B activity by different pharmacological inhibitors (i.e., parthenolide, MG132 and BAY 11-7082) and by overexpressed mutated I{kappa}B{alpha} prevented the activation of STAT1. To identify the factors involved, we performed macroarray cDNA profiling with or without inhibition of NF-{kappa}B. The expression of several cytokines was NF-{kappa}B dependent among those alpha and gamma IFNs (IFN-{alpha} and IFN-{gamma}), known activators of STAT1. By real-time PCR and enzyme-linked immunosorbent assay we show that IFN-{alpha} and IFN-{gamma} are expressed and released by LCLs in an NF-{kappa}B-dependent manner. Finally, the blocking of the IFN-{alpha} and IFN-{gamma} by neutralizing antibodies led to the complete inhibition of tyrosine phosphorylation of STAT1. Taken together, our results clearly show that LMP1-induced tyrosine phosphorylation of STAT1 is almost exclusively due to the NF-{kappa}B-dependent secretion of IFNs. Whether this response, which is usually considered to be antiviral, is in fact required for the persistence of the virus remains to be elucidated.

* Corresponding author. Mailing address: UPRES EA 34306, Service de Biochimie, AP-HP, Hôpital Avicenne, 125 Rue de Stalingrad, 93009 Bobigny Cedex, France. Phone: 33(0)1-48-95-59-28. Fax: 33(0)1-48-95-56-27. E-mail: remi.fagard{at}avc.ap-hop-paris.fr.

Journal of Virology, April 2005, p. 4936-4943, Vol. 79, No. 8
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.8.4936-4943.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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