title: Enhanced interleukin-4 production in CD4+ T cells and elevated immunoglobulin E levels in antigen-primed mice by bisphenol A and nonylphenol, endocrine disruptors: involvement of nuclear factor-AT and Ca2+.
abstract: Bisphenol A (BPA) and p-nonylphenol (NP) are representative endocrine disruptors (EDs) that may have adverse effects on human health. The influence of these compounds on allergic immune responses remains unclear. In this study, we have examined the effects of BPA and NP on production of interleukin-4 (IL-4), a pro-inflammatory cytokine closely associated with allergic immune responses. Both BPA and NP significantly enhanced IL-4 production in keyhole limpet haemocyanin (KLH)-primed CD4+ T cells in a concentration-dependent manner. Treatment with BPA or NP in vivo resulted in significant increase of IL-4 production in CD4+ T cells and of antigen-specific immunoglobulin E (IgE) levels in the sera of KLH-primed mice. Furthermore, BPA and NP enhanced the activation of IL-4 gene promoter in EL4 T cells transiently transfected with IL-4 promoter/reporter constructs, and the enhancing effect mapped to a region in the IL-4 promoter containing binding sites for nuclear factor (NF)-AT. Activation of T lymphocytes by phorbol 12-myristate 13-acetate/ionomycin resulted in markedly enhanced binding activities to the NF-AT site, which significantly increased upon addition of BPA or NP, as demonstrated by the electrophoretic mobility shift assay, indicating that the transcription factor NF-AT was involved in the enhancing effect of BPA and NP on IL-4 production. The enhancement of IL-4 production by BPA or NP was significantly reduced by nitrendipine, a blocker of Ca2+ influx, and by FK506, a calcineurin inhibitor. FK506 inhibited the NF-AT-DNA binding activity and IL-4 gene promoter activity enhanced by BPA or NP. These results represent the first report describing possible enhancement of allergic response by EDs through increasing IL-4 production in CD4+ T cells and antigen-specific IgE levels in the sera via the stimulation of Ca2+/calcineurin-dependent NF-AT activation.
authors.affiliation: Immunology Laboratory, College of Pharmacy, Chonnam National University, Kwangju, Republic of Korea.
authors.forename: Mee H
authors.initials: MH
authors.lastname: Lee
authors.forename: Su W
authors.initials: SW
authors.lastname: Chung
authors.forename: Bok Y
authors.initials: BY
authors.lastname: Kang
authors.forename: Jin
authors.initials: J
authors.lastname: Park
authors.forename: Choon H
authors.initials: CH
authors.lastname: Lee
authors.forename: Seung Y
authors.initials: SY
authors.lastname: Hwang
authors.forename: Tae S
authors.initials: TS
authors.lastname: Kim
mesh_terms: D000818:Animals; D001559:Benzhydryl Compounds; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D002118:Calcium / Q000276:immunology; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D004968:Estrogens, Non-Steroidal / Q000494:pharmacology*; D005260:Female; D007073:Immunoglobulin E / Q000097:blood; D015847:Interleukin-4 / Q000096:biosynthesis* / Q000235:genetics; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010636:Phenols / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000276:immunology; D014157:Transcription Factors / Q000276:immunology; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D002118:Calcium; D004268:DNA-Binding Proteins; D004968:Estrogens, Non-Steroidal; D007073:Immunoglobulin E; D015847:Interleukin-4; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010636:Phenols; D014157:Transcription Factors; C025256:nonylphenol; C006780:bisphenol A; D000098826:Bisphenol A Compounds