Suppression of human B cell activation by 2,3,7,8-tetrachlorodibenzo-p-dioxin involves altered regulation of B cell lymphoma-6.

The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) produces marked suppression of the primary humoral immune response in virtually every animal species evaluated thus far. In addition, epidemiological studies performed in areas of dioxin contamination have identified an association between TCDD exposure and an increased incidence of non-Hodgkin's lymphoma (NHL). Recent studies using an in vitro CD40 ligand model of human B cell differentiation have shown that TCDD impairs both B cell activation and differentiation. The present study extends these findings by identifying B cell lymphoma-6 [BCL-6] as a putative cellular target for deregulation by TCDD, which may contribute to suppression of B cell function as well as NHL. BCL-6 is a multifunctional transcriptional repressor frequently mutated in NHLs and known to regulate critical events of B cell activation and differentiation. In the presence of TCDD, BCL-6 protein levels were elevated and concurrently the same population of cells with high BCL-6 levels showed decreased CD80 and CD69 expression indicative of impaired cellular activation. The elevated BCL-6 levels resulted in a concomitant increase in BCL-6 DNA binding activity at its cognate binding site within an enhancer region for CD80. Furthermore, a small molecule inhibitor of BCL-6 activity reversed TCDD-mediated suppression of CD80 expression in human B cells. In the presence of a low-affinity ligand of the aryl hydrocarbon receptor (AHR), suppression of B cell activation and altered BCL-6 regulation were not observed. These results provide new mechanistic insights into the role of BCL-6 in the suppression of human B cell activation by TCDD.

[1]  S. Monti,et al.  The role of the aryl hydrocarbon receptor in normal and malignant B cell development , 2013, Seminars in Immunopathology.

[2]  A. Melnick,et al.  Lineage-specific functions of Bcl-6 in immunity and inflammation are mediated through distinct biochemical mechanisms , 2013, Nature Immunology.

[3]  Michele Pagano,et al.  FBXO11 targets BCL6 for degradation and is inactivated in diffuse large B-cell lymphomas , 2012, Nature.

[4]  N. Kaminski,et al.  2,3,7,8-Tetrachlorodibenzo-p-dioxin-mediated disruption of the CD40 ligand-induced activation of primary human B cells. , 2011, Toxicology and applied pharmacology.

[5]  N. Kaminski,et al.  The long winding road toward understanding the molecular mechanisms for B-cell suppression by 2,3,7,8-tetrachlorodibenzo-p-dioxin. , 2011, Toxicological sciences : an official journal of the Society of Toxicology.

[6]  N. Kaminski,et al.  Induction of the aryl hydrocarbon receptor-responsive genes and modulation of the immunoglobulin M response by 2,3,7,8-tetrachlorodibenzo-p-dioxin in primary human B cells. , 2010, Toxicological sciences : an official journal of the Society of Toxicology.

[7]  Alexander D. MacKerell,et al.  A small-molecule inhibitor of BCL6 kills DLBCL cells in vitro and in vivo. , 2010, Cancer cell.

[8]  Emily A. Stevens,et al.  The aryl hydrocarbon receptor: a perspective on potential roles in the immune system , 2009, Immunology.

[9]  F. Matsumura,et al.  A new cross-talk between the aryl hydrocarbon receptor and RelB, a member of the NF-kappaB family. , 2009, Biochemical pharmacology.

[10]  A. Melnick,et al.  Structure of a BCOR corepressor peptide in complex with the BCL6 BTB domain dimer. , 2008, Molecular cell.

[11]  R. Green,et al.  Bcl-6 mediates the germinal center B cell phenotype and lymphomagenesis through transcriptional repression of the DNA-damage sensor ATR , 2007, Nature Immunology.

[12]  Frédéric Mauny,et al.  A municipal solid waste incinerator as the single dominant point source of PCDD/Fs in an area of increased non-Hodgkin's lymphoma incidence. , 2007, Chemosphere.

[13]  D. Sherr,et al.  Constitutive Activation and Environmental Chemical Induction of the Aryl Hydrocarbon Receptor/Transcription Factor in Activated Human B Lymphocytes , 2005, Molecular Pharmacology.

[14]  Ryan T. Phan,et al.  The BCL6 proto-oncogene suppresses p53 expression in germinal-centre B cells , 2004, Nature.

[15]  G. Cattoretti,et al.  BCL6 Controls the Expression of the B7-1/CD80 Costimulatory Receptor in Germinal Center B Cells , 2003, The Journal of experimental medicine.

[16]  Ji-Yeon Yu,et al.  Immunotoxicological effects of Agent Orange exposure to the Vietnam War Korean veterans. , 2003, Industrial health.

[17]  H. Niu,et al.  The proto‐oncogene BCL‐6 in normal and malignant B cell development , 2002, Hematological oncology.

[18]  Maria Teresa Landi,et al.  Immunologic effects of dioxin: new results from Seveso and comparison with other studies. , 2002, Environmental health perspectives.

[19]  René Bernards,et al.  A senescence rescue screen identifies BCL6 as an inhibitor of anti-proliferative p19(ARF)-p53 signaling. , 2002, Genes & development.

[20]  Guomin Shan,et al.  Highly sensitive dioxin immunoassay and its application to soil and biota samples , 2001 .

[21]  G. Bishop,et al.  B lymphocyte activation by contact-mediated interactions with T lymphocytes. , 2001, Current opinion in immunology.

[22]  N. Kerkvliet,et al.  Aryl hydrocarbon receptor-deficient mice generate normal immune responses to model antigens and are resistant to TCDD-induced immune suppression. , 2001, Toxicology and applied pharmacology.

[23]  L. Staudt,et al.  BCL-6 represses genes that function in lymphocyte differentiation, inflammation, and cell cycle control. , 2000, Immunity.

[24]  N. Suciu-Foca,et al.  Cloning and functional characterization of the 5'-regulatory region of the human CD86 gene. , 2000, Human immunology.

[25]  K. Nephew,et al.  Activation of transcription factors activator protein-1 and nuclear factor-kappaB by 2,3,7,8-tetrachlorodibenzo-p-dioxin. , 2000, Biochemical pharmacology.

[26]  B. H. Ye,et al.  BCL-6 in the Pathogenesis of Non-Hodgkin's Lymphoma , 2000, Cancer investigation.

[27]  R. Dalla‐Favera,et al.  Antigen receptor signaling induces MAP kinase-mediated phosphorylation and degradation of the BCL-6 transcription factor. , 1998, Genes & development.

[28]  M. Kogevinas,et al.  Cancer mortality in workers exposed to phenoxy herbicides, chlorophenols, and dioxins. An expanded and updated international cohort study. , 1997, American journal of epidemiology.

[29]  J. Gustafsson,et al.  Aryl hydrocarbon receptor-mediated signal transduction. , 1997, Critical reviews in toxicology.

[30]  G. Freeman,et al.  A cell type-specific enhancer in the human B7.1 gene regulated by NF- kappaB , 1996, The Journal of experimental medicine.

[31]  J. Banchereau,et al.  Activated CD4+ T cells induce CD40-dependent proliferation of human B cell precursors. , 1994, Journal of immunology.

[32]  D. Morris,et al.  Direct effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on responses to lipopolysaccharide (LPS) by isolated murine B-cells. , 1993, Immunopharmacology.

[33]  D. Morris,et al.  Direct effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on human tonsillar lymphocytes. , 1993, Toxicology.

[34]  N. Andrews,et al.  A rapid micropreparation technique for extraction of DNA-binding proteins from limiting numbers of mammalian cells. , 1991, Nucleic acids research.

[35]  P. Lipsky,et al.  The role of B cell proliferation in the generation of immunoglobulin-secreting cells in man. , 1983, Journal of immunology.

[36]  A. Dent,et al.  Common mechanisms for the regulation of B cell differentiation and transformation by the transcriptional repressor protein BCL-6 , 2007, Immunologic research.

[37]  L. Staudt,et al.  Regulation of lymphocyte cell fate decisions and lymphomagenesis by BCL-6. , 1999, International reviews of immunology.

[38]  R. Dalla‐Favera,et al.  Molecular pathogenesis of B cell malignancy: the role of BCL-6. , 1999, Current topics in microbiology and immunology.

[39]  J. Banchereau,et al.  The CD40 antigen and its ligand. , 1994, Annual review of immunology.

[40]  D. Morris,et al.  Elucidation of cellular targets responsible for tetrachlorodibenzo-p-dioxin (TCDD)-induced suppression of antibody responses: I. The role of the B lymphocyte. , 1988, Immunopharmacology.