Putative link between transcriptional regulation of IgM expression by 2,3,7,8-tetrachlorodibenzo-p-dioxin and the aryl hydrocarbon receptor/dioxin-responsive enhancer signaling pathway

The B-cell, a major cellular component of humoral immunity, has been identi fied as a sensitive target of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). T he actual molecular mechanism responsible for the immunotoxic effects produ ced by TCDD is unclear; however, many of the biological effects produced by TCDD are thought to be mediated by the aryl hydrocarbon receptor (AhR). Us ing the CH12.LX B-cell line, the present studies show that inhibition of mu gene expression and IgM protein secretion by polychlorinated dibenzo-p-dio xin congeners follow a structure-activity relationship for AhR binding. Fur thermore, these effects may be mediated by the two dioxin-responsive enhanc er (DRE)-like sites that were identified within the Ig heavy chain 3' alpha -enhancer. Electrophoretic mobility shift assay-Western analysis demonstra ted TCDD-induced binding of the AhR nuclear complex to both DRE-like sites as well as TCDD-induced binding of several nuclear factor-kappaB/Rel protei ns to a kappaB site, which overlaps one of the DRE-like sites. Interestingl y, kappaB binding in the AhR-deficient BCL-1 B- cells was also induced by T CDD, demonstrating an AhR-independent effect of TCDD on kappaB binding. Tak en together, these results support an AhR/DRE- mediated mechanism for TCDD- induced inhibition of IgM expression.