The effect of 2, 3, 7, 8-Tetrachlorodibenzo -p-Dioxin in the human 3’IgH regulatory region and immunoglobulin expression. (IRC11P.440)

Abstract

Abstract The transcription of Ig heavy chain (Igh) is regulated by numerous regulatory elements including 3’Igh regulatory region (3’IghRR).Several transcription factors are involved in modulating the 3’IghRR and aryl hydrocarbon receptor (AhR). TCDD is an environmental contaminant and a ligand for AhR known to interfere with Immunoglobulins (Ig) expression in animal models. Our lab have identified in previous study the mouse 3’Ig heavy chain regulatory region (3’IgH RR) as a sensitive transcriptional target of TCDD, which inhibits mouse 3’IgH RR activation and induces AhR binding to dioxin response element (DRE) within 3’IgH RR. In human the hs1, 2 enhancer is polymorphic which has been correlated with several autoimmune diseases. We have identified TCDD-induced activation of the hu-hs1, 2 enhancer and a decrease in enhancer activity with deletion of the polymorphic region. Pervious study in our lab suggested that the hu-hs1, 2 enhancer may be a negative regulator of 3’IgH RR activity and Ig expression. The objective of this study is to study the cooperative effect of the Human 3’IgHRR Enhancers in intronic promoters and the possibility of TCDD interfering with this activity in the presence and absence of the stimulation and to study the polymorphic alleles effect in the human 3’IgHRR basal activity. We used human CL-01 B cell for this study and multiple luciferase reporter constructs driven by human Igγ intronic promoter and regulated by the human 3’IgHRR enhancers .