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Program in Immunology and Department of Surgery, Division of Transplantation, Stanford University, Stanford, CA 94305
EBV is a B lymphotrophic 
-herpesvirus that is associated with multiple human malignancies, including posttransplant lymphoproliferative disorder. The EBV-encoded protein, latent membrane protein 1 (LMP1), is required for oncogenic transformation of human B cells by EBV. An important consequence of LMP1 expression in EBV-infected B cells is the induction of cellular IL-10, which acts as an autocrine growth factor for B cell lymphomas. However, the mechanisms by which LMP1 induces IL-10 are incompletely understood. We previously showed that rapamycin, a clinically relevant immunosuppressant and mammalian target of rapamycin inhibitor, could suppress IL-10 production by EBV-infected B cell lines. To test the hypothesis that PI3K, which acts upstream of mammalian target of rapamycin, might also be involved in LMP1-dependent IL-10 production, we generated B cell lines expressing signaling-inducible chimeric LMP1. Our results show that induced LMP1 signaling elicits both p38- and PI3K-dependent IL-10 production in EBV– B cells. Moreover, distinct regions of the LMP1 signaling tail are associated with p38- vs PI3K-dependent IL-10 induction. We also demonstrate that the LMP1-dependent p38 and PI3K activation regulates IL-10 induction through discrete mechanisms. Whereas p38 activation is critical for the phosphorylation of the transcription factor CREB, PI3K activation is required for the inactivation of glycogen synthase kinase 3β (GSK3β), an inhibitory kinase that can regulate CREB function. We find that GSK3β regulates LMP1-dependent IL-10 induction, with GSK3β inhibition by pharmacologic or small interfering RNA strategies enhancing LMP1-induced IL-10 induction. These findings demonstrate that LMP1 uses both p38 and PI3K activation for maximal up-regulation of IL-10.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by an American Cancer Society postdoctoral fellowship (to S.L.L.), National Institutes of Health Grants AI41769 and CA105157 (to O.M.M.), and a grant from the Roche Organ Transplantation Research Foundation (to O.M.M.).
2 Address correspondence and reprint requests to Dr. Olivia M. Martinez, Department of Surgery, Division of Transplantation, Stanford University, MSLS Building Room P312, Stanford, CA 94305-5492. E-mail address: omm{at}stanford.edu
3 Abbreviations used in this paper: PTLD, posttransplant lymphoproliferative disorder; CTAR, C-terminal activating region; GSK, glycogen synthase kinase; LMP1, latent membrane protein 1; MAPKAP2, MARK-activated protein 2; mTOR, mammalian target of rapamycin; NGFR, nerve growth factor receptor; siRNA, small interfering RNA; TRAF, TNFR-associated factor.
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