title: Suppression of human B cell activation by 2,3,7,8-tetrachlorodibenzo-p-dioxin involves altered regulation of B cell lymphoma-6.
abstract: 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.
authors.affiliation: *Genetics Program, Center for Integrative Toxicology and Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan, 48824 *Genetics Program, Center for Integrative Toxicology and Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan, 48824.
authors.forename: Ashwini S
authors.initials: AS
authors.lastname: Phadnis-Moghe
authors.affiliation: *Genetics Program, Center for Integrative Toxicology and Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan, 48824 *Genetics Program, Center for Integrative Toxicology and Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan, 48824.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Crawford
authors.affiliation: *Genetics Program, Center for Integrative Toxicology and Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan, 48824 *Genetics Program, Center for Integrative Toxicology and Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan, 48824 kamins11@msu.edu.
authors.forename: Norbert E
authors.initials: NE
authors.lastname: Kaminski
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D018122:B7-1 Antigen / Q000235:genetics / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000187:drug effects / Q000378:metabolism; D001665:Binding Sites; D023201:CD40 Ligand / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D004785:Environmental Pollutants / Q000633:toxicity*; D006801:Humans; D007166:Immunosuppressive Agents / Q000633:toxicity*; D037181:Lectins, C-Type / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D051560:Proto-Oncogene Proteins c-bcl-6; D018336:Receptors, Aryl Hydrocarbon / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D018122:B7-1 Antigen; D051792:Basic Helix-Loop-Helix Proteins; D023201:CD40 Ligand; D004268:DNA-Binding Proteins; D004785:Environmental Pollutants; D007166:Immunosuppressive Agents; D037181:Lectins, C-Type; D000072317:Polychlorinated Dibenzodioxins; D051560:Proto-Oncogene Proteins c-bcl-6; D018336:Receptors, Aryl Hydrocarbon; D000099192:CD69 Antigens; C111235:AHR protein, human; C084103:BCL6 protein, human
keywords: AHR pathway; TCDD; immunotoxicity; impaired B cell activation