The Epstein-Barr virus latent membrane protein 1 induces interleukin-10 inBurkitt's lymphoma cells but not in Hodgkin's cells involving the p38/SAPK2 pathway

Infection of B cells with Epstein-Barr Virus (EBV) induces interleukin-10 ( IL-10) production, which may contribute to transformation. IL-10 can modula te the immune response at certain levels, playing a crucial role in balanci ng humoral and cellular responses. Moreover, it can function as a growth an d differentiation factor for B cells. However, the mechanism of IL-10 induc tion is still unclear. Here we demonstrate that IL-10 was specifically indu ced by the EBV-latent membrane protein 1 (LMP1) in Burkitt's lymphoma (BL) cell lines BL2 and BL41. In two T cell lines (Jurkat, MOLT3), two NHL cell lines (U266, MHH-PREB1), or three Hodgkin's disease (HD) cell lines (L428, L540, and KMH2), LMP1 did not induce IL-10 expression. In contrast, LMP1 ac tivated CD40 or CD54 (ICAM1) expression in the analyzed cell lines. LMP1 de rivatives lacking the C-terminal activation regions (CTAR), by deletion of the amino acids between 187 and 351 (Delta CTAR1) or 232 and 386 (Delta CTA R2), alone, or together induced IL-10 at very low amounts compared to wild- type LMP1. Inhibition of LMP1-mediated NF kappaB activation by constitutive repressive I kappaB-alpha only marginally impaired IL-10 expression in BL2 cells, while SB2035080 at 5 muM (a specific p38/SAPK2 inhibitor) led to re duced IL-10 expression. Our findings confirm the role of LMP1 in transactiv ation of cellular genes possibly important for tumor immunoescape but show that more than one signaling pathway is involved in this activation and sug gests the necessity of a defined conformation of CTARs to activate IL-10 in volving p38/SAPK2. (C) 2001 Academic Press.