The AhR and NF-κB/Rel Proteins Mediate the Inhibitory Effect of 2,3,7,8-Tetrachlorodibenzo-p-Dioxin on the 3' Immunoglobulin Heavy Chain Regulatory Region
The AhR and NF-κB/Rel Proteins Mediate the Inhibitory Effect of 2,3,7,8-Tetrachlorodibenzo-p-Dioxin on the 3' Immunoglobulin Heavy Chain Regulatory Region
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DOI：
10.1093/toxsci/kfv193
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发表时间：
2015-12-01
影响因子：
3.8
通讯作者：
Sulentic, Courtney E. W.
中科院分区：
文献类型：
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作者：
Salisbury, Richard L.;Sulentic, Courtney E. W.
鼠免疫球蛋白（IG）重链基因（Igh）的转录调控涉及几个调控元件，包括3 'Igh调节区（3' IghRR），其由至少4个增强子（hs 3A、hs 1.2、hs 3B和hs 4）组成。hs1.2和hs 4增强子表现出最大的转录活性，并含有几种转录因子的结合位点，包括核因子κ B/Rel（NF-κ B/Rel）蛋白和芳烃受体（AhR）。有趣的是，环境免疫抑制剂2，3，7，8-四氯二苯并-对-二恶英（TCDD），其有效地抑制抗体分泌，也深刻地抑制由B淋巴细胞活化剂脂多糖（LPS）诱导的3 'IghRR和hs1.2增强子活化，但增强LPS诱导的hs 4增强子活化。在hs 1.2和hs 4增强子内，AhR结合位点与NF-κ B/Rel结合位点非常接近或重叠，表明AhR和NF-κ B/Rel对3 'IghRR的潜在相互调节。本研究的目的是使用AhR配体TCDD、AhR拮抗剂CH 223191和Toll样受体激动剂LPS、Resiquimod（R848）或胞嘧啶-磷酸-鸟嘌呤-寡脱氧核苷酸（CpG）来评估NF-κ B/Rel和AhR对3 'IghRR及其增强剂的作用。利用表达3 'IghRR调节的转基因报告基因或诱导型I κ B α（抑制剂κ B-α蛋白）超阻遏物（I κ B α AA）的CH 12.LX B淋巴细胞系和变体，我们证明了3' IghRR和hs 4活性的AhR和NF-κ B/Rel依赖性调节。此外，在小鼠脾细胞或CH 12. LX细胞中，通过LPS和TCDD的共处理，AhR和NF-κ B/Rel蛋白RelA和RelB的hs1.2和hs 4增强子内的结合发生了差异性改变。这些结果表明，3 'IghRR内的AhR和NF-κ B/Rel蛋白结合谱介导了TCDD对IG表达的抑制作用，从而抑制了抗体水平。
Transcriptional regulation of the murine immunoglobulin (Ig) heavy chain gene (Igh) involves several regulatory elements including the 3'Igh regulatory region (3'IghRR), which is composed of at least 4 enhancers (hs3A, hs1.2, hs3B, and hs4). The hs1.2 and hs4 enhancers exhibit the greatest transcriptional activity and contain binding sites for several transcription factors including nuclear factor kappaB/Rel (NF-kappa B/Rel) proteins and the aryl hydrocarbon receptor (AhR). Interestingly, the environmental immunosuppressant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), which potently inhibits antibody secretion, also profoundly inhibits 3'IghRR and hs1.2 enhancer activation induced by the B-lymphocyte activator lipopolysaccharide (LPS), but enhances LPS-induced activation of the hs4 enhancer. Within the hs1.2 and hs4 enhancers, the AhR binding site is in close proximity or overlaps an NF-kappa B/Rel binding site suggesting a potential reciprocal modulation of the 3'IghRR by AhR and NF-kappa B/Rel. The objective of the current study was to evaluate the role of NF-kappa B/Rel and the AhR on the 3'IghRR and its enhancers using the AhR ligand TCDD, the AhR antagonist CH223191, and toll-like receptor agonists LPS, Resiquimod (R848), or cytosine-phosphate-guanine-oligodeoxynucleotides (CpG). Utilizing the CH12.LX B-lymphocyte cell line and variants expressing either a 3'IghRR-regulated transgene reporter or an inducible I kappa B alpha (inhibitor kappa B-alpha protein) superrepressor (I kappa B alpha AA), we demonstrate an AhR- and NF-kappa B/Rel-dependent modulation of 3'IghRR and hs4 activity. Additionally, in mouse splenocytes or CH12.LX cells, binding within the hs1.2 and hs4 enhancer of the AhR and the NF-kappa B/Rel proteins RelA and RelB was differentially altered by the cotreatment of LPS and TCDD. These results suggest that the AhR and NF-kappa B/Rel protein binding profile within the 3'IghRR mediates the inhibitory effects of TCDD on Ig expression and therefore antibody levels.