Reversal of EBV immortalization precedes apoptosis in IL-6-induced human B cell terminal differentiation.
Cell death in B cell terminal differentiation rapidly follows cell cycle arrest in IL-6 differentiation of EBV-immortalized, IgG-bearing human lymphoblastoid cells in vitro. G1 arrest is now found to coincide with repression of EBNA2 and LMP1, two EBV genes essential for B cell transformation, without activation of the viral lytic cycle. IL-6-differentiated B cells die by apoptosis, as evidenced by increases in Annexin V binding activity, PARP cleavage, and chromatin disorganization. Expression of Mcl-1, a Bcl-2 family member, was specifically induced during IL-6 differentiation and down-regulated during apoptosis. Thus, IL-6 reverses EBV immortalization and activates the terminal differentiation program in IgG-bearing human B lymphoblastoid cells, including regulation of an anti-apoptotic gene to coordinate differentiation, cell cycle arrest, and cell death.
Altmeyer
A
A
Department of Pathology, Cornell University Medical College, New York, New York 10021, USA.
Simmons
R C
RC
Krajewski
S
S
Reed
J C
JC
Bornkamm
G W
GW
Chen-Kiang
S
S
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000166:cytology* / Q000821:virology; D002144:Callithrix; D002454:Cell Differentiation / Q000187:drug effects; D002472:Cell Transformation, Viral / Q000187:drug effects*; D002478:Cells, Cultured; D019309:Epstein-Barr Virus Nuclear Antigens / Q000235:genetics; D016193:G1 Phase; D015967:Gene Expression Regulation, Viral / Q000187:drug effects*; D004854:Herpesvirus 4, Human / Q000235:genetics*; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics; D010950:Plasma Cells / Q000166:cytology; D019253:Proto-Oncogene Proteins c-bcl-2; D014763:Viral Matrix Proteins / Q000378:metabolism
C037662:EBV-associated membrane antigen, Epstein-Barr virus; D019309:Epstein-Barr Virus Nuclear Antigens; D015850:Interleukin-6; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014763:Viral Matrix Proteins