Involvement of Blimp-1 and AP-1 dysregulation in the 2,3,7,8-Tetrachlorodibenzo-p-dioxin-mediated suppression of the IgM response by B cells.
B cell differentiation and humoral immune responses are markedly suppressed by the persistent environmental contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The suppression of humoral immune responses by TCDD occurs by direct actions on the B cell and involves activation of the aryl hydrocarbon receptor. Transcriptional regulation of paired box gene 5 (Pax5), an important regulator of B cell differentiation, is altered by TCDD in concordance with the suppression of B cell differentiation and humoral immunoglobulin M response. We hypothesized that TCDD treatment leads to dysregulation of Pax5 transcription by interfering with the basic B cell differentiation mechanisms and aimed to determine the effects of TCDD on upstream regulators of Pax5. A critical regulator of B cell differentiation, B lymphocyte-induced maturation protein-1 (Blimp-1) acts as a transcriptional repressor of Pax5. In lipopolysaccharide (LPS)-activated murine B cell lymphoma, CH12.LX, Blimp-1 messenger RNA, and DNA-binding activity within the Pax5 promoter were suppressed by TCDD. Furthermore, LPS activation of CH12.LX cells upregulated DNA-binding activity of activator protein 1 (AP-1) at three responsive element-like motifs within the Blimp-1 promoter. TCDD treatment of LPS-activated CH12.LX cells suppressed AP-1 binding to these motifs between 24 and 72 h, in concordance with the suppression of Blimp-1 by TCDD. A more comprehensive analysis at 72 h demonstrated that the suppression of AP-1 binding within the Blimp-1 promoter by TCDD was concentration dependent. In summary, our findings link the TCDD-mediated suppression of Blimp-1 through AP-1 to the dysregulation of Pax5, which ultimately leads to the suppression of B cell differentiation and humoral immune responses.
Schneider
Dina
D
Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA.
Manzan
Maria A
MA
Yoo
Byung Sun
BS
Crawford
Robert B
RB
Kaminski
Norbert
N
D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology*; D002460:Cell Line; D024202:Electrophoretic Mobility Shift Assay; D007075:Immunoglobulin M / Q000096:biosynthesis*; D007166:Immunosuppressive Agents; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008156:Luciferases / Q000235:genetics; D051379:Mice; D051757:PAX5 Transcription Factor / Q000235:genetics; D010957:Plasmids / Q000235:genetics; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D018336:Receptors, Aryl Hydrocarbon / Q000096:biosynthesis / Q000235:genetics; D020218:Response Elements; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000166:cytology / Q000276:immunology; D018808:Transcription Factor AP-1 / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D014162:Transfection
D007075:Immunoglobulin M; D007166:Immunosuppressive Agents; D008070:Lipopolysaccharides; D051757:PAX5 Transcription Factor; C497282:Pax5 protein, mouse; D000072317:Polychlorinated Dibenzodioxins; C513258:Prdm1 protein, mouse; D018336:Receptors, Aryl Hydrocarbon; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D008156:Luciferases; D000074462:Positive Regulatory Domain I-Binding Factor 1