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.
Jones
Richard J
RJ
Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
Seaman
William T
WT
Feng
Wen-Hei
WH
Barlow
Elizabeth
E
Dickerson
Sarah
S
Delecluse
Henri-Jacque
HJ
Kenney
Shannon C
SC
D000818:Animals; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D020031:Epstein-Barr Virus Infections / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism; D015151:Immunoblotting; D016753:Interleukin-10 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism*; D008232:Lymphoproliferative Disorders / Q000378:metabolism / Q000821:virology*; D051379:Mice; D016513:Mice, SCID; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D014412:Tumor Virus Infections / Q000378:metabolism / Q000821:virology*; D014763:Viral Matrix Proteins / Q000378:metabolism; D014764:Viral Proteins / Q000378:metabolism
C068382:BRLF1 protein, Human herpesvirus 4; C063676:BZLF1 protein, Herpesvirus 4, Human; D004268:DNA-Binding Proteins; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D017874:Immediate-Early Proteins; D015850:Interleukin-6; D015534:Trans-Activators; D014763:Viral Matrix Proteins; D014764:Viral Proteins; D016753:Interleukin-10