Modulation of the human polymorphic hs1,2 enhancer within the 3′IgH regulatory region by TCDD

Abstract

2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) is a potent environmental toxin known to inhibit immunoglobulin (Ig) gene expression. Transcriptional regulation of the Ig heavy chain (IgH) involves the 3′IgH regulatory region (3′IgHRR) and its enhancers (hs3, hs1,2, and hs4) which contain DNA binding sites for several transcription factors including NF‐κB and dioxin response elements (DRE). TCDD induces binding of the aryl hydrocarbon receptor complex to DREs within the 3′IgHRR and inhibits murine 3′IgHRR activation in a well characterized mouse B‐cell line (CH12.LX). In humans, a polymorphism of the hs1,2 enhancer resulting in varying numbers of a 53 bp sequence has been correlated with autoimmune diseases like IgA nephropathy and Celiac disease. The repeated sequence contains κB and DRE binding sites. The objective of this study was to comparatively evaluate the effect of TCDD and LPS on human and mouse hs1,2 enhancers in the CH12.LX model. In transient luciferase studies, an increased number of repeats in the human hs1,2 enhancer increased the sensitivity to LPS. Interestingly, TCDD also markedly enhanced human hs1,2 activity and even augmented LPS‐induced activation. This starkly contrasted with TCDD‐induced inhibition of the mouse hs1,2 and 3′IgHRR in LPS‐stimulated CH12.LX cells suggesting a species difference in IgH transcriptional regulation.(Supported by NIEHS R01ES014676)