Roles of lytic viral infection and IL-6 in early versus late passage lymphoblastoid cell lines and EBV-associated lymphoproliferative disease.

Lytically infected EBV-positive lymphoblastoid cells enhance the growth of early-passage, but not late-passage, EBV-immortalized lymphoblastoid cell lines (LCLs) in SCID mice and have enhanced IL-6 secretion. Here, we have examined the importance of IL-6 for the growth of early-passage LCLs (EPL) in SCID mice, identified lytic EBV proteins that activate IL-6 production and compared viral and cellular differences between early versus late passage LCLs (LPL). IL-6 was required for efficient growth of EPL in SCID mice. The EBV immediate-early (IE) proteins, BRLF1 and BZLF1, each induced IL-6 secretion when transfected into 293 and BJAB cells. Interestingly, the combination of BZLF1 and the latent EBV protein, LMP-1, induced much more IL-6 expression in both 293 and BJAB cells than either protein alone. Both BZLF1 and BRLF1 also enhanced IL-10 production in 293 cells. In comparison to the EPL, LPL had much reduced expression of early lytic viral proteins and cellular IL-6. In contrast, expression of cellular IL-10 was similar in EPL versus LPL, while VEGF secretion was increased in late-passage LCLs. These results suggest that both BRLF1 and BZLF1 contribute to IL-6 secretion in lytically infected cells and that lytically infected cells may promote early lymphoproliferative disease in patients through enhanced IL-6 production.