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Autocrine lymphotoxin production in Epstein–Barr virus-immortalized B cells: induction via NF-κB activation mediated by EBV-derived latent membrane protein 1

Leukemia volume 17, pages 2196–2201 (2003)Cite this article

Abstract

Epstein–Barr virus (EBV)-immortalized lymphoblastoid cells express high levels of lymphotoxin and use this molecule as an autocrine growth factor. We hypothesized that the EBV-derived latent membrane protein 1 (LMP1) mediates lymphotoxin production by inducing NF-κB binding to the lymphotoxin promoter. We assessed lymphotoxin production, LMP1 expression, and NF-κB activation in Z-43 (EBV-positive lymphoblastoid cells), Daudi (EBV-positive Burkitt's cells), and 3A4 (EBV-negative Burkitt's cells containing a stably transfected tetracycline-inducible LMP1 construct). Z-43 cells expressed high levels of LMP1 (immunoblot) and lymphotoxin (ELISA); the EBV-positive Burkitt's lymphoma line Daudi expressed neither LMP1 nor lymphotoxin. Similarly, induction of LMP1 in the 3A4 cells (exposed to tetracycline) was accompanied by a 13-fold increase in lymphotoxin levels (ELISA) as compared to uninduced (LMP1-negative) cells. EMSAs demonstrated high levels of NF-κB activation in Z-43 and tetracycline-induced 3A4 cells, but much lower levels in the uninduced 3A4 cells. Exposure of these cells to Bay 11-7082 (an inhibitor of IκB phosphorylation and, therefore, NF-κB activation) abrogated NF-κB binding and lymphotoxin production in a dose-dependent manner in both Z-43 and 3A4 cells. Therefore, in our model system, autocrine lymphotoxin production is largely driven by NF-κB activation, which is in turn mediated by EBV-derived LMP1 signaling.

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  1. Department of Bioimmunotherapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    M P Thompson, B B Aggarwal, S Shishodia, Z Estrov & R Kurzrock

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Thompson, M., Aggarwal, B., Shishodia, S. et al. Autocrine lymphotoxin production in Epstein–Barr virus-immortalized B cells: induction via NF-κB activation mediated by EBV-derived latent membrane protein 1. Leukemia 17, 2196–2201 (2003). https://doi.org/10.1038/sj.leu.2403130

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