Thomas Brown (Committee Member), David Cool (Committee Member), Courtney Sulentic (Advisor)
Master of Science (MS)
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a potent environmental toxin that inhibits immunoglobulin (Ig) gene expression in mice. Transcriptional regulation of the Ig heavy chain (IgH) involves the 3'IgH regulatory region (3'IgH RR). The murine 3'IgH RR consists of four enhancers (hs3A, hs1,2, hs3B, and hs4), which are homologous to the human 3'IgH RR enhancers (hs3, hs1,2, and hs4). In humans, a polymorphism of the hs1,2 enhancer, resulting in a varying number of tandem repeats of a 53 bp sequence, has been correlated with autoimmune diseases like IgA nephropathy and Celiac disease. The repeated sequence contains a kB and DRE binding site. Previous studies have shown that TCDD inhibits the murine 3'IgH RR but activates the hs4 enhancer in a well-characterized mouse B-cell line, CH12.LX. Therefore, the objective of the current study was to determine if TCDD inhibits the murine 3'IgH RR by repressing hs1,2 enhancer activity and if this effect will be mirrored by the human polymorphic hs1,2 enhancer in the CH12.LX model. Using transient luciferase studies and CH12.LX cells that stably express a transgene under the regulation of the hs1,2/hs3A enhancer pair, we have found that indeed the mouse hs1,2 enhancer is inhibited by TCDD in LPS-induced B cells. However the human hs1,2 undergoes a striking activation after TCDD treatment, much like the murine hs4 enhancer. These results suggest a difference in transcriptional regulation between the mouse and human hs1,2 sequence. Mutational analyses determined that DRE, kB, AP-1, and Oct binding motifs found within the human hs1,2 enhancer act in concert to mediate TCDD-induced activation of the human polymorphic hs1,2 enhancer. Since TCDD represents a large class of chemicals found in the environment, diet, and pharmaceuticals, understanding chemical-induced modulation of the 3'IgH RR enhancers may provide a clue to the etiology of certain autoimmune diseases.
Department or Program
Department of Pharmacology and Toxicology
Year Degree Awarded
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