scholarly journals Regulation of B-cell growth and immunoglobulin gene transcription by interleukin-6

Blood ◽  
1992 ◽  
Vol 79 (2) ◽  
pp. 452-459 ◽  
Author(s):  
JE Tanner ◽  
G Tosato
Keyword(s):  
B Cells ◽  
B Cell ◽  
Interleukin 6 ◽  
Cell Activation ◽  
Cell Number ◽  
Immunoglobulin Gene ◽  
Rna Transcription ◽  
Barr Virus ◽  
Dna And Rna ◽  
Cycle Dependent

Interleukin-6 (IL-6) stimulates growth and immunoglobulin (lg) secretion in Epstein-Barr virus (EBV)-infected B cells. In this study, we demonstrate that B-cell activation by IL-6 is associated with an initial induction of c-myc, a gene believed to act as a competence factor for increased RNA transcription and DNA replication, and by increases in DNA, RNA, and protein synthesis, as well as cell number. IL-6 increased the levels of lg mRNA per cell in comparison to a non- cycle-dependent cellular mRNA, tubulin. However, two other cell cycle- dependent cellular mRNAs, c-myc and actin, were also induced by IL-6 comparable to lg mRNAs. Increased levels of lg mRNA were not due to significant changes in RNA turnover, but appeared to reflect increased levels of RNA transcription. Together, these findings support the notion that IL-6 plays an important role as a stimulator of DNA and RNA synthesis in EBV-activated B cells.

scholarly journals Regulation of B-cell growth and immunoglobulin gene transcription by interleukin-6

Blood ◽  
1992 ◽  
Vol 79 (2) ◽  
pp. 452-459 ◽  
Author(s):  
JE Tanner ◽  
G Tosato
Keyword(s):  
B Cells ◽  
B Cell ◽  
Interleukin 6 ◽  
Cell Activation ◽  
Cell Number ◽  
Immunoglobulin Gene ◽  
Rna Transcription ◽  
Barr Virus ◽  
Dna And Rna ◽  
Cycle Dependent

Abstract Interleukin-6 (IL-6) stimulates growth and immunoglobulin (lg) secretion in Epstein-Barr virus (EBV)-infected B cells. In this study, we demonstrate that B-cell activation by IL-6 is associated with an initial induction of c-myc, a gene believed to act as a competence factor for increased RNA transcription and DNA replication, and by increases in DNA, RNA, and protein synthesis, as well as cell number. IL-6 increased the levels of lg mRNA per cell in comparison to a non- cycle-dependent cellular mRNA, tubulin. However, two other cell cycle- dependent cellular mRNAs, c-myc and actin, were also induced by IL-6 comparable to lg mRNAs. Increased levels of lg mRNA were not due to significant changes in RNA turnover, but appeared to reflect increased levels of RNA transcription. Together, these findings support the notion that IL-6 plays an important role as a stimulator of DNA and RNA synthesis in EBV-activated B cells.

scholarly journals Early events in Epstein-Barr virus infection provide a model for B cell activation.

1985 ◽  
Vol 162 (1) ◽  
pp. 45-59 ◽  
Author(s):  
D A Thorley-Lawson ◽  
K P Mann
Keyword(s):  
B Cells ◽  
B Cell ◽  
Epstein Barr Virus ◽  
Rna Synthesis ◽  
Cell Activation ◽  
Nuclear Antigen ◽  
Epstein Barr Virus Infection ◽  
B Cell Activation ◽  
Barr Virus ◽  
Epstein Barr

We have used Epstein-Barr virus (EBV) infection in vitro to delineate two distinct stages in B cell activation. Previous studies have shown that the BLAST-2 (EBVCS) (EBV cell surface) activation antigen is expressed on a small fraction of B cells within 24 h of stimulation with a variety of agents, including mitogens and EBV. In this study, we have been able to isolate the BLAST-2 (EBVCS)+ cells early after activation/infection with EBV. These cells are small B cells that are actively synthesizing RNA but not DNA, and are, therefore, clearly distinct from large proliferating lymphoblasts. In addition, they contain multiple copies of the EBV genome, express the viral nuclear antigen (EBNA) and, most importantly, proceed to undergo transformation when placed back in culture. By comparison, the BLAST-2 (EBVCS)- population does not undergo transformation, even though a fraction of these cells are activated for RNA synthesis and express EBNA. Thus, using the EBV system, we have been able to show directly that an activated B cell first expresses the BLAST-2 (EBVCS) antigen concomitant with an increase in RNA synthesis, and then subsequently proceeds to differentiate into a proliferating lymphoblast.

scholarly journals Studies of in vitro activated CD5+ B cells

Blood ◽  
1989 ◽  
Vol 73 (1) ◽  
pp. 202-208 ◽  
Author(s):  
AS Freedman ◽  
G Freeman ◽  
J Whitman ◽  
J Segil ◽  
J Daley ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
B Lymphocytes ◽  
Cell Activation ◽  
Tritiated Thymidine ◽  
Interleukin 1 ◽  
Cell Subpopulation ◽  
Recombinant Interferon ◽  
Barr Virus

Abstract Human B lymphocytes undergo distinct phenotypic changes following activation with antigen and polyclonal mitogens. Increasing interest has focused on the unique subpopulation of B cells that expresses the CD5 antigen. In this study, we examined the signals that induce the expression of CD5 on normal splenic B cells. Only 12-O- tetradecanoylphorbol-13-acetate (TPA) induced CD5 expression on highly purified splenic B cells, whereas anti-immunoglobulin (anti-Ig), Epstein-Barr virus, anti-CD20, recombinant interleukin-1 (rIL-1), rIL- 2, rIL-4, recombinant interferon-gamma (rINF-gamma), and B-cell growth factor all failed to induce CD5 expression. The expression of CD5 was detected on the cell surface by 48 hours and decreased by 96 hours. Dual-fluorochrome analysis demonstrated that the CD5+ B cells coexpressed the B-cell activation antigens B5, IL-2 receptor, and CD23, thereby providing phenotypic evidence that this B-cell subpopulation is activated. In vitro studies of dual-fluorochrome-sorted, TPA-stimulated splenic B cells demonstrated significantly greater tritiated thymidine incorporation and Ig secretion by the CD20+ CD5- cells than by the CD20+ CD5+ subset. These phenotypic and functional studies are consistent with the notion that TPA-induced CD5+ B cells are a subset of in vitro activated B lymphocytes.

scholarly journals Manipulation of the Toll-Like Receptor 7 Signaling Pathway by Epstein-Barr Virus

2007 ◽  
Vol 81 (18) ◽  
pp. 9748-9758 ◽  
Author(s):  
Heather J. Martin ◽  
Jae Myun Lee ◽  
Dermot Walls ◽  
S. Diane Hayward
Keyword(s):  
Cell Proliferation ◽  
B Cells ◽  
B Cell ◽  
Epstein Barr Virus ◽  
Cell Activation ◽  
B Cell Activation ◽  
Toll Like Receptor ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr

ABSTRACT Epstein-Barr virus (EBV) infection of primary B cells causes B-cell activation and proliferation. Activation of B cells requires binding of antigen to the B-cell receptor and a survival signal from ligand-bound CD40, signals that are provided by the EBV LMP1 and LMP2A latency proteins. Recently, Toll-like receptor (TLR) signaling has been reported to provide a third B-cell activation stimulus. The interaction between the EBV and TLR pathways was therefore investigated. Both UV-inactivated and untreated EBV upregulated the expression of TLR7 and downregulated the expression of TLR9 in naive B cells. UV-inactivated virus transiently stimulated naive B-cell proliferation in the presence of the TLR7 ligand R837, while addition of the TLR7 antagonist IRS 661 impaired cell growth induced by untreated EBV. Interferon regulatory factor 5 (IRF-5) is a downstream mediator of TLR7 signaling. IRF-5 was induced following EBV infection, and IRF-5 was expressed in B-cell lines with type III latency. Expression of IRF-5 in this setting is surprising since IRF-5 has tumor suppressor and antiviral properties. B-cell proliferation assays provided evidence that EBV modulates TLR7 signaling responses. Examination of IRF-5 transcripts identified a novel splice variant, V12, that was induced by EBV infection, was constitutively nuclear, and acted as a dominant negative form in IRF-5 reporter assays. IRF-4 negatively regulates IRF-5 activation, and IRF-4 was also present in type III latently infected cells. EBV therefore initially uses TLR7 signaling to enhance B-cell proliferation and subsequently modifies the pathway to regulate IRF-5 activity.

scholarly journals Kaposi's Sarcoma-Associated Herpesvirus Latency Locus Compensates for Interleukin-6 in Initial B Cell Activation

2015 ◽  
Vol 90 (4) ◽  
pp. 2150-2154 ◽  
Author(s):  
Sang-Hoon Sin ◽  
Sun Ah Kang ◽  
Yongbaek Kim ◽  
Anthony Eason ◽  
Kelly Tan ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Interleukin 6 ◽  
Cell Activation ◽  
Marginal Zone ◽  
Kaposi Sarcoma ◽  
B Cell Activation ◽  
Marginal Zone B Cells ◽  
Survival Factor

Interleukin 6 (IL-6) is considered a proliferation and survival factor for B cells. To assess the role of IL-6 in Kaposi sarcoma-associated herpesvirus (KSHV) latency, KSHV latency locus-transgenic mice (referred to as latency mice) lacking IL-6 were evaluated. IL-6−/−latency mice had the same phenotypes as the latency mice, i.e., increased frequency of marginal zone B cells, hyperplasia, and hyperglobulinemia, indicating that the KSHV latency locus, which includes all viral microRNAs (miRNAs), can compensate for lack of IL-6 in premalignant B cell activation.

scholarly journals Limiting dilution analysis of Epstein-Barr virus-induced immunoglobulin production by human B cells.

1983 ◽  
Vol 157 (1) ◽  
pp. 1-14 ◽  
Author(s):  
R Yarchoan ◽  
G Tosato ◽  
R M Blaese ◽  
R M Simon ◽  
D L Nelson
Keyword(s):  
B Cells ◽  
B Cell ◽  
Peripheral Blood ◽  
Epstein Barr Virus ◽  
Cell Activation ◽  
B Cell Activation ◽  
Barr Virus ◽  
Human B Cells ◽  
Epstein Barr ◽  
Limiting Dilution

The Epstein-Barr virus (EBV) is a herpes virus that has the capacity to infect human B cells and to induce them to secrete immunoglobulin (Ig). In the current experiments, Poisson analysis of limiting dilution cultures has been used to study the activation of human peripheral B cells by the B95-8 strain of EBV. Under the culture conditions used, 0.2-1% of peripheral blood B cells were activated by EBV to secrete IgM or IgG. In addition, when multiple replicate cultures containing limited numbers of B cells were tested for IgM and for IgG production, the precursors for IgM and IgG segregated independently; thus, individual B cell precursors matured into cells secreting IgM or IgG but not both classes of Ig. Additional experiments using limiting dilutions of EBV were undertaken to study the viral requirements for B cell activation. These studies indicated that B cell activation by EBV to produce Ig was consistent with a "one-hit" model and inconsistent with a "two-hit" model. Taken together, these results indicate that infection by one EBV virion is sufficient to induce a precursor peripheral blood B cell to secrete Ig and that only one isotype of Ig is then secreted.

scholarly journals Rheumatoid Factors Induce Signaling from B Cells, Leading to Epstein-Barr Virus and B-Cell Activation

2004 ◽  
Vol 78 (18) ◽  
pp. 9918-9923 ◽  
Author(s):  
Lixin Yang ◽  
Masayuki Hakoda ◽  
Kazuya Iwabuchi ◽  
Tsuyoshi Takeda ◽  
Takao Koike ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Epstein Barr Virus ◽  
Cell Activation ◽  
Mononuclear Cells ◽  
Rheumatoid Factors ◽  
B Cell Activation ◽  
Barr Virus ◽  
Membrane Bound ◽  
Epstein Barr

ABSTRACT B-cell antigen receptor signaling is initiated upon binding of the antigen to membrane-bound immunoblobulin (Ig), and the anti-Ig antibody (Ab) mimics this signaling. In B cells latently infected with Epstein-Barr virus (EBV), the same signals induce virus activation. We examine here whether rheumatoid factors (RFs), autoantibodies directed against the Fc portion of IgG, induce EBV and B-cell activation. As a source of RFs, RF-producing lymphoblastoid cell line (LCL) clones were isolated from peripheral blood mononuclear cells (PBMC) and synovial cells from patients with rheumatoid arthritis (RA) by EBV transformation. Burkitt's lymphoma-derived Akata cells, which are highly responsive to EBV activation by anti-Ig Abs, were used for the assay of EBV activation. Akata cells expressed IgG3 as membrane-bound Ig. RFs from a synovium-derived LCL were directed to IgG3 and induced EBV activation in 16 to 18% of Akata cells, whereas RFs from another synovium-derived LCL were directed to IgG1 and did not induce EBV activation. Pretreatment of RFs with the purified Fc fragment of human IgG completely abolished EBV activation. Furthermore, B-cell activation was assessed by incorporation of [3H]thymidine. RFs from synovium-derived LCLs efficiently induced B-cell activation, and the addition of CD40 ligand had a synergistic effect. On the other hand, RFs from PBMC-derived LCLs were polyreactive, had a lower affinity to IgG, and did not induce EBV and B-cell activation. The present findings imply a possible role for RFs as EBV and B-cell activators.

scholarly journals Studies of in vitro activated CD5+ B cells

Blood ◽  
1989 ◽  
Vol 73 (1) ◽  
pp. 202-208
Author(s):  
AS Freedman ◽  
G Freeman ◽  
J Whitman ◽  
J Segil ◽  
J Daley ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
B Lymphocytes ◽  
Cell Activation ◽  
Tritiated Thymidine ◽  
Interleukin 1 ◽  
Cell Subpopulation ◽  
Recombinant Interferon ◽  
Barr Virus

Human B lymphocytes undergo distinct phenotypic changes following activation with antigen and polyclonal mitogens. Increasing interest has focused on the unique subpopulation of B cells that expresses the CD5 antigen. In this study, we examined the signals that induce the expression of CD5 on normal splenic B cells. Only 12-O- tetradecanoylphorbol-13-acetate (TPA) induced CD5 expression on highly purified splenic B cells, whereas anti-immunoglobulin (anti-Ig), Epstein-Barr virus, anti-CD20, recombinant interleukin-1 (rIL-1), rIL- 2, rIL-4, recombinant interferon-gamma (rINF-gamma), and B-cell growth factor all failed to induce CD5 expression. The expression of CD5 was detected on the cell surface by 48 hours and decreased by 96 hours. Dual-fluorochrome analysis demonstrated that the CD5+ B cells coexpressed the B-cell activation antigens B5, IL-2 receptor, and CD23, thereby providing phenotypic evidence that this B-cell subpopulation is activated. In vitro studies of dual-fluorochrome-sorted, TPA-stimulated splenic B cells demonstrated significantly greater tritiated thymidine incorporation and Ig secretion by the CD20+ CD5- cells than by the CD20+ CD5+ subset. These phenotypic and functional studies are consistent with the notion that TPA-induced CD5+ B cells are a subset of in vitro activated B lymphocytes.

scholarly journals Interleukin-6 and Epstein-Barr virus induction by cyclosporine A: potential role in lymphoproliferative disease

Blood ◽  
1994 ◽  
Vol 84 (11) ◽  
pp. 3956-3964 ◽  
Author(s):  
JE Tanner ◽  
J Menezes
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cyclosporine A ◽  
Interleukin 6 ◽  
Epstein Barr Virus ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Lytic Cycle ◽  
Barr Virus ◽  
Epstein Barr

Posttransplant patients undergoing prolonged cyclosporine A (CsA) immunosuppressive therapy have been reported to have increased incidence of Epstein-Barr virus (EBV)-associated lymphoproliferative disorders. We undertook experiments to analyze the possible actions of CsA during EBV-infection of human peripheral blood mononuclear cells (PBMC). EBV-infected B cells cultured with CsA demonstrated increased EBV B-cell outgrowth as compared with those cultured without CsA. PBMC, after infection with EBV and CsA treatment, demonstrated increased interleukin-6 (IL-6) activity in the culture supernatant. The induction of IL-6 appears to differ within the various lymphocyte populations. In monocytes, IL-6 expression appears preferentially induced by EBV and is initiated by the binding of the two major virion glycoproteins, gp350 and gp220. Expression of IL-6 in T cells appears to be due mainly to CsA. B cells also express IL-6 after EBV exposure, but not after CsA treatment. EBV-immortalized B-cell lines cultured with CsA exhibited both an increased number of cells expressing viral lytic-cycle antigens and increased amounts of lytic-cycle proteins. IL-6, which is induced by CsA in PBMC, was also capable of inducing the lytic viral cycle in several EBV-immortalized cells. CsA, in promoting both increased numbers of lytic EBV B cells and an EBV paracrine factor, IL-6, within the microenvironment of EBV B cell:T cell and EBV B cell:monocyte interactions, may result in increased EBV B-cell immortalization and ultimately lead to the promotion of B-cell lymphomas in immunosuppressed patients.

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